Submissions for variant NM_001035.3(RYR2):c.6280G>A (p.Gly2094Ser)

gnomAD frequency: 0.00012  dbSNP: rs777365708

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000241874	SCV000319573	uncertain significance	Cardiovascular phenotype	2023-06-21	criteria provided, single submitter	clinical testing	The p.G2094S variant (also known as c.6280G>A), located in coding exon 41 of the RYR2 gene, results from a G to A substitution at nucleotide position 6280. The glycine at codon 2094 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000351653	SCV000356331	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001093824	SCV000356332	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000523894	SCV000616858	uncertain significance	not provided	2020-05-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001093824	SCV001199697	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2094 of the RYR2 protein (p.Gly2094Ser). This variant is present in population databases (rs777365708, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 263982). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170255	SCV001332815	uncertain significance	Cardiomyopathy	2018-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170255	SCV001358494	uncertain significance	Cardiomyopathy	2022-12-06	criteria provided, single submitter	clinical testing	This variant is located in 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 21/280548 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.