Submissions for variant NM_001035.3(RYR2):c.12858C>T (p.Ser4286=)

gnomAD frequency: 0.00004  dbSNP: rs185482345

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182647	SCV000235023	benign	not specified	2014-10-31	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589602	SCV000697606	benign	not provided	2016-10-31	criteria provided, single submitter	clinical testing	Variant summary: The c.12858C>T (p.Ser4286=) in RYR2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control population dataset of ExAC at a frequency of 0.00009 (11/120046 chrs tested), exclusively in individuals of East Asian descent (0.0013; 11/8480 chrs tested). These frequencies exceed the estimated maximal expected allele frequency of a pathogenic variant in RYR2 gene (0.00005). The variant has not, to our knowledge, been reported in affected individuals , but was cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001099835	SCV000760712	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778051	SCV000914166	benign	Cardiomyopathy	2018-09-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099835	SCV001256323	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001099836	SCV001256324	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
All of Us Research Program, National Institutes of Health	RCV003996737	SCV004818683	benign	Catecholaminergic polymorphic ventricular tachycardia	2023-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004658979	SCV005158786	likely benign	Cardiovascular phenotype	2024-03-24	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.