Submissions for variant NM_001035.3(RYR2):c.7619A>G (p.His2540Arg)

gnomAD frequency: 0.00072  dbSNP: rs200105499

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036792	SCV000060447	uncertain significance	not specified	2013-01-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The His2540Arg vari ant in RYR2 has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.2% (7/4062) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200105499). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) do not provide strong support for or against an impact to the protein. In summ ary, although the frequency of this variant suggests that it is more likely beni gn, it is too low to confidently rule out a disease-causing role and additional information is needed to fully assess its clinical significance.
GeneDx	RCV000766722	SCV000235265	uncertain significance	not provided	2022-07-18	criteria provided, single submitter	clinical testing	Reported in an adult with HCM who also harbored additional cardiogenetic variants (Mademont-Soler et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 28771489, 19926015, 28404607)
Ambry Genetics	RCV000252890	SCV000318659	likely benign	Cardiovascular phenotype	2021-09-07	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.
Invitae	RCV002513440	SCV000554606	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036792	SCV000918170	benign	not specified	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.7619A>G (p.His2540Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 277206 control chromosomes, predominantly at a frequency of 0.0021 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 84 fold of 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 African origin. c.7619A>G has been reported in the literature in individuals affected with Cardiomyopathy (Landstrom_2017, Mademon-Soler_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170261	SCV001332821	benign	Cardiomyopathy	2018-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170261	SCV001341200	likely benign	Cardiomyopathy	2018-12-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534780	SCV004760687	likely benign	RYR2-related disorder	2022-01-16	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).