Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182660 | SCV000235038 | likely pathogenic | not provided | 2023-04-18 | criteria provided, single submitter | clinical testing | Identified in a large Newfoundland family with index cases experiencing catecholaminergic polymorphic ventricular tachycardia (CPVT) or sudden cardiac arrest (Lauson et al., 2014); extensive family genotyping and phenotyping revealed numerous carriers who were asymptomatic or had a history of syncope, indicating substantial phenotypic variability and lower than previously reported penetrance (Tung et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34760626, 31994352, 19926015) |
| Ambry Genetics | RCV000620075 | SCV000736257 | likely pathogenic | Cardiovascular phenotype | 2016-06-06 | criteria provided, single submitter | clinical testing | The p.R176L variant (also known as c.527G>T), located in coding exon 8 of the RYR2 gene, results from a G to T substitution at nucleotide position 527. The arginine at codon 176 is replaced by leucine, an amino acid with dissimilar properties. Although the p.R176L variant has not been reported previously, another alteration at the same position in RYR2, p.R176Q, has been identified in multiple individuals with arrhythmias (Tester DJ et al. Heart Rhythm. 2005;2(10):1099-105; Haugaa KH et al. Europace. 2010;12(3):417-23; Medeiros-Domingo A et al. J Am Coll Cardiol. 2009;54(22):2065-74). Furthermore, this alteration has been reported as occurring in a disease-associated hotspot loop of the RYR2 protein (Amador FJ et al. Proc Natl Acad Sci U.S.A. 2009;106(27):11040-4). The RYR2 p.R176L variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6101 samples (12202 alleles) with coverage at this position. This amino acid position is completely conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |