Submissions for variant NM_001035.3(RYR2):c.3537T>C (p.Gly1179=)

gnomAD frequency: 0.00001  dbSNP: rs397516526

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036732	SCV000060387	likely benign	not specified	2012-05-17	criteria provided, single submitter	clinical testing	Gly1179Gly in exon 29 of RYR2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and it is not located within the splice consensus sequence. Gly1179Gly in exon 29 of RYR2 (allele fre quency = n/a)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001093861	SCV000285722	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000036732	SCV000345749	benign	not specified	2016-09-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000408233	SCV000356269	likely benign	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 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	RCV001093861	SCV000356270	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	RCV000036732	SCV000514440	benign	not specified	2015-05-08	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171192	SCV001333887	benign	Cardiomyopathy	2018-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171192	SCV001352900	benign	Cardiomyopathy	2018-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036732	SCV001362145	benign	not specified	2019-04-16	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.3537T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00086 in 249076 control chromosomes, predominantly at a frequency of 0.0069 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 115 fold of 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 populations of South Asian origin. To our knowledge, no occurrence of c.3537T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as uncertain significance and three times as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002453309	SCV002616176	benign	Cardiovascular phenotype	2020-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
All of Us Research Program, National Institutes of Health	RCV003996274	SCV004816988	benign	Catecholaminergic polymorphic ventricular tachycardia	2024-01-09	criteria provided, single submitter	clinical testing