ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14311G>A (p.Val4771Ile) (rs794728804)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182845 SCV000235233 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The V4771I pathogenic variant in the RYR2 gene has been reported previously in association with CPVT (Priori etal., 2002; Postma et al., 2005; Kawamura et al., 2013). V4771I was initially reported by Priori et al. (2002) as a denovo variant in a 6 year-old boy with CPVT. V4771I has since been reported in two sisters with CPVT/polymorphicventricular tachycardia, and in at least one Japanese individual with CPVT (Postma et al., 2005; Kawamura et al.,2013). V4771I has also been reported in one asymptomatic relative of one of the previously reported affectedindividuals harboring V4771I (Hayashi et al., 2012). Collectively, V4771I was absent from 1,500 published controlalleles (Priori et al., 2002; Postma et al., 2005; Kawamura et al., 2013). Additionally, V4771I was not observed inapproximately 6,000 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. Furthermore, this variant has beenobserved as assumed de novo in two probands referred to GeneDx for CPVT testing. Finally, the V4771I variant islocated in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variantsoccur (Medeiros-Domingo et al., 2009), and this substitution occurs at a position that is conserved across species.
Ambry Genetics RCV000245608 SCV000320063 likely pathogenic Inborn genetic diseases 2015-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000475330 SCV000541672 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 4771 of the RYR2 protein (p.Val4771Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several unrelated individuals affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 12093772, 19926015, 21292648, 26114861). It has also been shown to segregate with the phenotype in an additional family (PMID: 23595086). ClinVar contains an entry for this variant (Variation ID: 201357). For these reasons, this variant has been classified as Pathogenic.

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