Submissions for variant NM_001035.3(RYR2):c.9560A>G (p.Lys3187Arg)

gnomAD frequency: 0.00137  dbSNP: rs184218219

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036807	SCV000060462	likely benign	not specified	2012-02-09	criteria provided, single submitter	clinical testing	Lys3187Arg in exon 67 of RYR2: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (12/3078) of African American c hromosomes by the NHLBI Exome Sequencing Project in a broad population (http://e vs.gs.washington.edu/EVS; dbSNP rs184218219). Lys3187Arg in exon 67 of RYR2 (rs 184218219; allele frequency = 0.4%, 12/3078) **
GeneDx	RCV001703875	SCV000235012	likely benign	not provided	2020-10-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780, 25351510)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239266	SCV000296980	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2015-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV002513445	SCV000554562	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036807	SCV000697634	likely benign	not specified	2021-08-22	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.9560A>G (p.Lys3187Arg) 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 0.00025 in 235202 control chromosomes, predominantly at a frequency of 0.0039 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 65 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 African or African-American origin. c.9560A>G has been reported in the literature as a likely benign variant in one individual affected with dilated cardiomyopathy (DCM) (example, Pugh_2014). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 benign (n=1)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000620711	SCV000734935	likely benign	Cardiovascular phenotype	2019-03-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000777798	SCV000913790	likely benign	Cardiomyopathy	2018-09-10	criteria provided, single submitter	clinical testing