Submissions for variant NM_001035.3(RYR2):c.9923A>G (p.Asn3308Ser)

gnomAD frequency: 0.00030  dbSNP: rs201081663

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182641	SCV000235015	likely benign	not specified	2016-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515054	SCV000285756	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-11-17	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000182641	SCV000740450	likely benign	not specified	2017-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191841	SCV001359755	likely benign	Cardiomyopathy	2018-11-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182641	SCV001482034	likely benign	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.9923A>G (p.Asn3308Ser) 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 0.00039 in 244926 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 11.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.9923A>G has been reported in the literature, without strong evidence for causality (Landstrom_2017, Marjamaa_2009, Medeiros-Domingo_2009). The variant was reported experimentally to have open probabilities similar to the wild type channels in vitro (Marjamaa_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001311694	SCV001501972	benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	RYR2: BP4, BS1, BS2
Ambry Genetics	RCV002381510	SCV002691028	likely benign	Cardiovascular phenotype	2019-10-29	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.
Fulgent Genetics, Fulgent Genetics	RCV002492610	SCV002800214	likely benign	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-12	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157463	SCV000207207	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-04-17	no assertion criteria provided	clinical testing