Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002551504 | SCV001205586 | likely pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2019-01-29 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.7009G>C) giving rise to the same protein effect observed here (p.Gly2337Arg) has been determined to be pathogenic (PMID: 28750076, Invitae). This suggests that this variant is also likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RYR2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 2337 of the RYR2 protein (p.Gly2337Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |
| Ambry Genetics | RCV002363578 | SCV002661958 | uncertain significance | Cardiovascular phenotype | 2022-09-01 | criteria provided, single submitter | clinical testing | The p.G2337R variant (also known as c.7009G>A), located in coding exon 46 of the RYR2 gene, results from a G to A substitution at nucleotide position 7009. The glycine at codon 2337 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). A different variant (c.7009G>C) with the same protein effect was detected in a patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Forleo C et al. PLoS One, 2017 Jul;12:e0181842). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |