ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2828T>C (p.Leu943Ser) (rs373665895)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182703 SCV000235083 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing The L943S variant of uncertain significance in the RYR2 gene has previously been reported in association with HCM (Lopes et al., 2015). The L943S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, L943S is not located in one of the three hot spots regions in the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, the Exome Aggregation Consortium (ExAC) reports L943S was observed in 12/35,496 alleles from individuals of European (Non-Finnish) ancestry and 3/4,056 alleles from individuals of European (Finnish) ancestry (Lek et al., 2016).
Invitae RCV000639042 SCV000760601 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 943 of the RYR2 protein (p.Leu943Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs373665895, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 201232). 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 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000182703 SCV000924925 uncertain significance not provided 2017-08-16 no assertion criteria provided provider interpretation

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