Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478561 | SCV000568209 | pathogenic | not provided | 2022-01-12 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant results in channel dysfunction leading to arrhythmia (Jiang et al., 2002; Wehrens et al., 2003); Multiple other studies have utilized mouse models carrying the RYR2 R4496C variant (equivalent to R4497C human variant) to demonstrate that R4496C results in an increased propensity for triggered arrhythmia (Cerrone et al., 2005; Liu et al., 2006; Sedej et al., 2010); Reported in ClinVar (ClinVar Variant ID# 12957; ClinVar); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 19926015, 11208676, 19226252, 24025405, 27452199, 16828071, 15544015, 18006488, 12169647, 20080988, 16339485, 12919952, 16825580, 21742998, 16239587, 12093772, 29453246, 31737537, 12837242, 15890976, 29434162) |
Invitae | RCV000013823 | SCV000637512 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-10-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4497 of the RYR2 protein (p.Arg4497Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant RYR2-related conditions (PMID: 11208676, 12093772, 15544015, 29434162, 29453246; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12169647, 12837242, 12919952, 15890976, 16339485, 20080988, 20538074, 26666913). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV000617445 | SCV000738219 | pathogenic | Cardiovascular phenotype | 2017-11-03 | criteria provided, single submitter | clinical testing | The p.R4497C pathogenic mutation (also known as c.13489C>T), located in coding exon 93 of the RYR2 gene, results from a C to T substitution at nucleotide position 13489. The arginine at codon 4497 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and has also been shown to segregate with disease in affected family members (Priori SG et al. Circulation 2001 Jan;10(2):196-200; Priori et al. Circulation 2002 Jul;113(7):829-40; Kawata H et al. Circ. J. 2016 Aug;80(9):1907-15). A multitude of publications investigating the functional consequences of the R4496C mutation have been performed in the mouse which is equivalent to R4497C in humans (Wehrens XH et al. Cell 2003 Jun;113(7):829-40; George CH et al. Circ. Res. 2003 Sept;93(6):531-40; Jiang D et al. Circ. Res. 2005 Nov;97(11):1173-81; Zissimopoulos S et al. Biochem. J. 2009 Apr;419(2):273-8). The R4496C mouse mutation was shown to be responsible for the bidirectional and polymorphic VT observed in knock-in mice (Cerrone M et al. Circ. Res. 2005 May;96(10):e77-82). Furthermore, a recent in vitro study showed that allele specific silencing by RNA interference prevents life threatening arrhythmias in heterozygous R4496C mice (Bongianino R et al. Circ. Res. 2017 Aug;121(5):525-536). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
CHEO Genetics Diagnostic Laboratory, |
RCV003149571 | SCV003838728 | pathogenic | Cardiomyopathy | 2021-07-19 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000478561 | SCV004226724 | pathogenic | not provided | 2022-08-03 | criteria provided, single submitter | clinical testing | PP1_moderate, PP2, PP3, PM2_supporting, PS3, PS4 |
OMIM | RCV000013823 | SCV000034070 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2001-01-16 | no assertion criteria provided | literature only | |
Gene |
RCV000013823 | SCV000057857 | not provided | Catecholaminergic polymorphic ventricular tachycardia 1 | no assertion provided | literature only |