Submissions for variant NM_001035.3(RYR2):c.828A>G (p.Arg276=)

gnomAD frequency: 0.00086  dbSNP: rs180711819

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000361184	SCV000356197	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV001093847	SCV000356198	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV001718598	SCV000514431	likely benign	not provided	2020-01-29	criteria provided, single submitter	clinical testing
Invitae	RCV001093847	SCV000637621	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621348	SCV000737729	likely benign	Cardiovascular phenotype	2016-09-23	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768757	SCV000900127	likely benign	Cardiomyopathy	2016-06-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432303	SCV000918164	benign	not specified	2018-02-06	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.828A>G alters a non-conserved nucleotide resulting in a synonymous change (p.Arg276Arg) and 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 48-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in population(s) of African origin. To our knowledge, the variant, c.828A>G, has not been reported in affected individuals via publications. However, multiple clinical diagnostic laboratories via ClinVar submissions (evaluated after 2014) classify the variant as "likely benign/benign" or "uncertain significance". Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000768757	SCV001343046	benign	Cardiomyopathy	2018-11-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004543169	SCV004762584	likely benign	RYR2-related disorder	2020-03-05	criteria provided, single submitter	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).
All of Us Research Program, National Institutes of Health	RCV003995805	SCV004845293	benign	Catecholaminergic polymorphic ventricular tachycardia	2024-02-05	criteria provided, single submitter	clinical testing