ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8378G>A (p.Arg2793Gln) (rs559773178)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182881 SCV000235269 uncertain significance not provided 2014-09-18 criteria provided, single submitter clinical testing p.Arg2793Gln (CGG>CAG): c.8378 G>A in exon 56 of the RYR2 gene (NM_001035.2). The R2793Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R2793Q variant was not observed in approximately 4,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2793Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved within mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY, ARRHYTHMIA panel(s).
Invitae RCV000699888 SCV000828618 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2793 of the RYR2 protein (p.Arg2793Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs559773178, ExAC 0.05%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201391). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.

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