ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10381A>G (p.Met3461Val)

gnomAD frequency: 0.00038  dbSNP: rs147512481
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171766 SCV000055288 likely benign not provided 2013-06-24 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV002515253 SCV000637473 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620370 SCV000734909 likely benign Cardiovascular phenotype 2020-01-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000171766 SCV000970916 likely benign not provided 2020-02-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001180037 SCV001344885 likely benign Cardiomyopathy 2018-12-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194069 SCV001363325 benign not specified 2019-10-15 criteria provided, single submitter clinical testing Variant summary: RYR2 c.10381A>G (p.Met3461Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248876 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 72 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.10381A>G has been reported in the literature in individuals with limited information (Ng_2013, Landstrom_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Three ClinVar submissions (evaluation after 2014) cite the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences RCV004739553 SCV005350983 likely benign RYR2-related disorder 2024-04-17 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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