Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002549075 | SCV002309833 | likely pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2021-10-05 | 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. 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. This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 391 of the RYR2 protein (p.Ala391Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. |
| Ambry Genetics | RCV002331653 | SCV002627899 | likely pathogenic | Cardiovascular phenotype | 2022-04-18 | criteria provided, single submitter | clinical testing | The p.A391D variant (also known as c.1172C>A), located in coding exon 14 of the RYR2 gene, results from a C to A substitution at nucleotide position 1172. The alanine at codon 391 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.A391D is more disruptive to the MIR domain of RYR2 than a nearby internally pathogenic variant (Borko L et al. Acta Crystallogr D Biol Crystallogr, 2014 Nov;70:2897-912). 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. |