ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1240C>T (p.Arg414Cys) (rs764698152)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182678 SCV000235057 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene.The R414C variant was previously published in a 16-year-old female who died while swimming competitively, and it was absent from 400 controls (Creighton et al., 2006). The R414C variant was subsequently reported in a 10-year-old boy who was experiencing ventricular fibrillation during a swimming race (Moray et al., 2011). The R414C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R414C 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. The R414C variant is 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). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to arginine are tolerated across species. While another variant at this same residue (R414L) and variants in nearby residues (S406L, R407S, S413T, T415R, I419F) have been reported in HGMD in association with CPVT (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Finally, the R414C variant is classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000230388.1; Landrum et al., 2016).
Ambry Genetics RCV000251690 SCV000320388 uncertain significance Cardiovascular phenotype 2017-07-21 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000639093 SCV000760654 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 414 of the RYR2 protein (p.Arg414Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs764698152, ExAC 0.01%). This variant has been reported in two individuals affected with exercise-induced cardiac events (PMID: 15887426, 21478052). ClinVar contains an entry for this variant (Variation ID: 201212). Experimental studies have shown that this missense change does not affect the calcium sensitivity of RYR2 channels (PMID: 23152493). A different missense substitution at this codon (p.Arg414Leu) has been reported in individuals affected with exercise-induced cardiac events (PMID: 15466642, 16188589). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182678 SCV001147748 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
Color RCV001186513 SCV001352962 uncertain significance Cardiomyopathy 2020-01-22 criteria provided, single submitter clinical testing

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