ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13081G>A (p.Glu4361Lys) (rs794728795)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182830 SCV000235217 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing The E4361K variant of uncertain significance in the RYR2 gene has notbeen published as pathogenic or been reported as benign to our knowledge. However, this variant hasbeen observed in one other unrelated individual referred for ARVC genetic testing at GeneDx. This variant is not observed in large population cohorts(Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E4361Kvariant is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. This substitutionoccurs at a position that is conserved in mammal. Furthermore, the E4361K variant is located in oneof the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variantsoccur (Medeiros-Domingo et al., 2009). However, in silico analysis is inconsistent in its predictions asto whether or not the variant is damaging to the protein structure/function.
Invitae RCV000463901 SCV000541656 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 4361 of the RYR2 protein (p.Glu4361Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201343). This variant occurs within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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