ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1775G>A (p.Gly592Glu) (rs794728724)

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Total submissions: 3
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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 RCV000691530 SCV000819314 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-03-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 592 of the RYR2 protein (p.Gly592Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201222). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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 RCV001189918 SCV001357303 uncertain significance Cardiomyopathy 2020-04-27 criteria provided, single submitter clinical testing

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