ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.527G>T (p.Arg176Leu) (rs794728708)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182660 SCV000235038 likely pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing The R176L likely pathogenic variant in the RYR2 gene was previously identified in a female with a history of two cardiac arrests whose son had bidirectional VT suggestive of catecholaminergic polymorphic ventricular tachycardia (CPVT) (Lauson et al., 2014). This variant was identified in 16 individuals from 4 generations of this large Newfoundland family; however, at least two relatives also harbored a variant in the KCNQ1 gene and segregation analysis is limited by the clinical information provided (Lauson et al., 2014). At least two other carriers of only the R176L variant were symptomatic with cardiac arrest or bidirectional VT, while the carrier father of the proband was asymptomatic at 76 years of age (Lauson et al., 2014). The R176L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R176L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, the R176L variant is located in the N-Terminal domain, 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, a different missense variant at the same codon (R176Q) has been reported in association with CPVT, also described as ARVD2" in some publications (Tiso et al., 2001; Bauce et al., 2002; Tester et al., 2005; Haugaa et al., 2010). 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; thus, they concluded that R176Q is sufficient to cause catecholamine-induced VT. However, to our knowledge no studies have been performed to determine the functional effect of the R176L variant."
Ambry Genetics RCV000620075 SCV000736257 likely pathogenic Cardiovascular phenotype 2016-06-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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