Submissions for variant NM_001035.3(RYR2):c.5654G>C (p.Gly1885Ala)

dbSNP: rs41315858

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537034	SCV000936468	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001525050	SCV001735051	uncertain significance	Cardiomyopathy	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 1885 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 cardiovascular disorders in the literature. This variant has been identified in 2/245448 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	RCV002345761	SCV002652971	uncertain significance	Cardiovascular phenotype	2021-08-23	criteria provided, single submitter	clinical testing	The p.G1885A variant (also known as c.5654G>C), located in coding exon 37 of the RYR2 gene, results from a G to C substitution at nucleotide position 5654. The glycine at codon 1885 is replaced by alanine, an amino acid with similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002507378	SCV002816784	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001606	SCV004820167	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 1885 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 cardiovascular disorders in the literature. This variant has been identified in 2/245448 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.
GeneDx	RCV004721609	SCV005327028	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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: 19926015, 23861362)