ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11836G>A (p.Gly3946Ser) (rs794728777)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182800 SCV000235186 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The G3946S pathogenic variant in the RYR2 gene has been reported in multiple unrelated individuals with CPVT (Priori et al., 2002; Mok et al., 2006; Wilde et al., 2008; Hayashi et al., 2009; van der Werf et al., 2011; Kawamura et al., 2013; Yu et al., 2016). Additionally, this variant has been reported as a de novo variant in two patients with CPVT (Ohno et al., 2015). This variant results in a non-conservative acid substitution. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies in cultured cells suggest that this variant alters the cytosolic Ca2+ activation of the RYR2 channel, which the authors propose leads to cardiac dysfunction (Xiao et al., 2016). The G3946S 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). Furthermore, the G3946S variant is not observed in large population cohorts (Lek et al., 2016). In summary, G3946S in the RYR2 gene is interpreted as a pathogenic variant.
Invitae RCV000460954 SCV000541707 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2017-05-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 3946 of the RYR2 protein (p.Gly3946Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs794728777, ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 12093772, 21616285, 23595086, 26114861). This variant has been also shown to arise de novo in individuals affected with CPVT (PMID: 26114861). ClinVar contains an entry for this variant (Variation ID: 201315). 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. For these reasons, this variant has been classified as Pathogenic.

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