Submissions for variant NM_001035.3(RYR2):c.8378G>A (p.Arg2793Gln)

gnomAD frequency: 0.00014  dbSNP: rs559773178

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182881	SCV000235269	uncertain significance	not provided	2014-09-18	criteria provided, single submitter	clinical testing	p.Arg2793Gln (CGG>CAG): c.8378 G>A in exon 56 of the RYR2 gene (NM_001035.2). The R2793Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R2793Q variant was not observed in approximately 4,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2793Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved within mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY, ARRHYTHMIA panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516912	SCV000828618	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190681	SCV001358244	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2793 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 5/153128 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002433806	SCV002680193	likely benign	Cardiovascular phenotype	2023-12-12	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.
All of Us Research Program, National Institutes of Health	RCV003996799	SCV004823354	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2793 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 5/153128 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004539706	SCV004783428	likely benign	RYR2-related disorder	2023-05-26	no assertion criteria provided	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).