Submissions for variant NM_001035.3(RYR2):c.6134A>G (p.Glu2045Gly)

dbSNP: rs878854160

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519787	SCV000285739	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2045 of the RYR2 protein (p.Glu2045Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 29453246). ClinVar contains an entry for this variant (Variation ID: 238238). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375500	SCV001572346	uncertain significance	not specified	2021-04-06	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.6134A>G (p.Glu2045Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 248958 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6134A>G has been reported in the literature in individual(s) affected with Catecholaminergic Polymorphic Ventricular Tachycardia (e.g. Medeiros-Domingo_2009, Kapplinger_2018). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. A co-occurrence with a likely pathogenic variant has been reported (RYR2 c.13528G>A, p.A4510T; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001524824	SCV001734784	uncertain significance	Cardiomyopathy	2020-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 2045 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 been reported in an individual suspected of having catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015). This variant has not been identified 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	RCV002354647	SCV002657026	uncertain significance	Cardiovascular phenotype	2016-01-19	criteria provided, single submitter	clinical testing	The p.E2045G variant (also known as c.6134A>G), located in coding exon 40 of the RYR2 gene, results from an A to G substitution at nucleotide position 6134. The glutamic acid at codon 2045 is replaced by glycine, an amino acid with some similar properties. The variant was reported once in a cohort of subjects with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Medeiros-Domingo A, J. Am. Coll. Cardiol. 2009 Nov; 54(22):2065-74). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6037 samples (12074 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species; however, glycine is the reference amino acid in two 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.