Submissions for variant NM_001035.3(RYR2):c.8798T>G (p.Val2933Gly)

gnomAD frequency: 0.00002  dbSNP: rs550691734

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103767	SCV000541677	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000520735	SCV000616859	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	Reported in association with sudden cardiac arrest, however, detailed clinical information was not provided (PMID: 29884292); 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 (PMID: 19926015); This variant is associated with the following publications: (PMID: 29884292, 19926015)
Color Diagnostics, LLC DBA Color Health	RCV001186329	SCV001352722	uncertain significance	Cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 2933 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 38/279924 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	RCV002374739	SCV002687881	likely benign	Cardiovascular phenotype	2021-06-30	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	RCV004000619	SCV004819118	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 2933 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 38/279924 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.