ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14885A>G (p.Tyr4962Cys) (rs794728832)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182895 SCV000235284 likely pathogenic not provided 2011-12-15 criteria provided, single submitter clinical testing This variant is denoted Tyr4962Cys (aka Y4962C) at the protein level and c.14885 A>G at the cDNA level. The Tyr4962Cys variant in the RYR2 gene results in a semi-conservative amino acid substitution of a neutral, polar Tyrosine residue with a neutral, polar Cysteine that can affect disulfide bonds and protein structure. In addition, Tyrs4962 is a highly conserved position throughout evolution. In silico analysis predicts Tyr4962Cys is damaging to the protein structure/function (Adzhubei IA et al., 2010; Schwarz JM et al., 2011). Furthermore, Tyr4962Cys was reported in a genotype-positive individual with a family history of CPVT (van der Werf et al., 2011). The NHLBI ESP Exome Variant Server reports Tyr4962Cys was not observed in approximately 4,700 individuals from European and African American backgrounds, indicating it is not a common benign polymorphism in these populations. Nevertheless, Tyr4962Cys does not reside in one of the three mutation hot spot regions of the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, we cannot definitively determine the clinical significance of the Tyr4962Cys variant, though evidence suggests it is disease-causing. The variant is found in CPVT panel(s).
Invitae RCV000704694 SCV000833652 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2018-04-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 4962 of the RYR2 protein (p.Tyr4962Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of catecholaminergic polymorphic ventricular tachycardia (CPVT) (Invitae). This variant has also been reported in an individual referred for testing for CPVT (PMID: 22787013). ClinVar contains an entry for this variant (Variation ID: 201405). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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