Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002534413 | SCV000832329 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2412 of the RYR2 protein (p.Gly2412Arg). This variant is present in population databases (rs550534270, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 580011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Color Diagnostics, |
RCV001181823 | SCV001347059 | uncertain significance | Cardiomyopathy | 2023-10-13 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 2412 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 7/249082 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Gene |
RCV001759402 | SCV002006845 | uncertain significance | not provided | 2021-04-05 | criteria provided, single submitter | clinical testing | Reported in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017); however, clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 580011; Landrum et al., 2016); 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: 28404607) |
Ambry Genetics | RCV002369947 | SCV002672429 | uncertain significance | Cardiovascular phenotype | 2019-12-04 | criteria provided, single submitter | clinical testing | The p.G2412R variant (also known as c.7234G>A), located in coding exon 48 of the RYR2 gene, results from a G to A substitution at nucleotide position 7234. The glycine at codon 2412 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |