ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.527G>A (p.Arg176Gln) (rs794728708)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208033 SCV000264177 pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2015-05-04 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000208033 SCV000299264 pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000182659 SCV000235037 pathogenic not provided 2018-03-09 criteria provided, single submitter clinical testing The R176Q pathogenic variant in the RYR2 gene has been reported previously in association with LQTS and CPVT, also described as ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Berge et al., 2008; Haugaa et al., 2010). The R176Q variant was initially reported by Tiso et al. (2001) in three relatives with exercise induced arrhythmia. The affected relatives in this family also carried a second variant in the RYR2 gene, on the same allele as the R176Q variant (in cis) (Tiso et al., 2001). However, Tester et al. (2005) and Berge et al. (2008) identified the R176Q variant in isolation in two unrelated patients with a history of syncope and prolonged or borderline prolonged QT intervals. The R176Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R176Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In addition, the R176Q 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). Finally, while there have been different functional mechanisms suggested for the R176Q variant (Thomas et al., 2004; Jiang et al., 2005; Kannankeril et al., 2006; Zissimopoulos et al., 2009; Mathur et al., 2009), Kannankeril et al. (2006) reported that mice heterozygous for the R176Q variant developed frequent PVCs with isoproterenol while the wild-type mice did not and concluded that R176Q is sufficient to cause catecholamine-induced VT."
Invitae RCV000549173 SCV000637574 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 176 of the RYR2 protein (p.Arg176Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with catecholaminergic polymorphic ventricular tachycardia (PMID: 20106799), and in an individual with catecholaminergic polymorphic ventricular tachycardia in whom this variant was observed to be de novo (Invitae). This variant also has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in a family where a second RYR2 variant (p.Thr2504Met) was also found in all affected individuals (PMID: 11159936). In addition, this variant has been observed in individuals referred for long QT syndrome genetic testing (PMID: 16188589, 18752142). ClinVar contains an entry for this variant (Variation ID: 201194). Experimental studies have shown that transgenic mice containing this missense change develop symptoms of catecholaminergic polymorphic ventricular tachycardia (PMID: 16873551, 20157052, 27482086). For these reasons, this variant has been classified as Pathogenic.

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