ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8060G>A (p.Ser2687Asn) (rs202020477)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520895 SCV000620571 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The S2687N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the S2687N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and asparagine is the wild-type amino acid at this position in multiple species. The S2687N 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). Furthermore, in silico analysis suggests this variant likely does not alter the protein structure/function.
Invitae RCV000701382 SCV000830182 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 2687 of the RYR2 protein (p.Ser2687Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs202020477, ExAC 0.03%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 451818). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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