Submissions for variant NM_001035.3(RYR2):c.4740G>A (p.Pro1580=)

gnomAD frequency: 0.00119  dbSNP: rs79811945

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036756	SCV000060411	benign	not specified	2015-02-18	criteria provided, single submitter	clinical testing	p.Pro1580Pro in exon 36 of RYR2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 5.5% (379/6868) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs79811945).
Eurofins Ntd Llc (ga)	RCV000036756	SCV000203479	benign	not specified	2013-11-26	criteria provided, single submitter	clinical testing
Invitae	RCV001093875	SCV000285732	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000036756	SCV000306062	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251724	SCV000318244	benign	Cardiovascular phenotype	2016-03-03	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina	RCV001093875	SCV000356297	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.
Illumina Laboratory Services, Illumina	RCV000260040	SCV000356298	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768767	SCV000900137	benign	Cardiomyopathy	2016-06-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768767	SCV000902736	benign	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036756	SCV001363327	benign	not specified	2019-03-18	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.4740G>A 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 0.0032 in 273374 control chromosomes, predominantly at a frequency of 0.042 within the East Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1680-folds higher than 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 East Asian origin. To our knowledge, no occurrence of c.4740G>A in individuals affected with Cardiomyopathy 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 as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001705664	SCV001845869	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing