ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8798T>G (p.Val2933Gly) (rs550691734)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520735 SCV000616859 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The V2933G variant has not been published as pathogenic or been reported as benign to our knowledge. The V2933G variant is observed in 25/30660 (0.08%) alleles from individuals of South Asian ancesty in large population cohorts (Lek et al., 2016). The V2933G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The V2933G variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Nevertheless, this substitution occurs at a position where only amino acids with similar properties to valine (V) are tolerated across species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000470159 SCV000541677 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-10-18 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 2933 of the RYR2 protein (p.Val2933Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs550691734, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 404201). 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 and their clinical significance is uncertain. This variant does not occur 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). In summary, this variant has uncertain impact on RYR2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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