Submissions for variant NM_001035.3(RYR2):c.1775G>A (p.Gly592Glu)

gnomAD frequency: 0.00001  dbSNP: rs794728724

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182689	SCV000235068	uncertain significance	not specified	2017-11-10	criteria provided, single submitter	clinical testing	p.Gly592Glu (GGA>GAA): c.1775 G>A in exon 18 of the RYR2 gene (NM_001035.2). The Gly592Glu variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly592Glu results in a non-conservative amino acid substitution of a non-polar Glycine with a negatively charged Glutamic acid at a position that is conserved across species. In silico analysis predicts Gly592Glu is possibly damaging to the protein structure/function. The Gly592Glu variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, Gly592Glu does not occur in one of the mutation hot spot" regions of the RYR2 gene (Medeiros-Domingo A et al., 2009). With the clinical and molecular information available at this time, we cannot definitively determine if Gly592Glu is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s)."
Invitae	RCV002515322	SCV000819314	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 592 of the RYR2 protein (p.Gly592Glu). This variant is not present in population databases (gnomAD no frequency). 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: 201222). 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) performed at Invitae 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.
Color Diagnostics, LLC DBA Color Health	RCV001189918	SCV001357303	uncertain significance	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 592 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 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	RCV002399661	SCV002711885	uncertain significance	Cardiovascular phenotype	2020-01-24	criteria provided, single submitter	clinical testing	The p.G592E variant (also known as c.1775G>A), located in coding exon 18 of the RYR2 gene, results from a G to A substitution at nucleotide position 1775. The glycine at codon 592 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is 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.