Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002516216 | SCV002252149 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-11-01 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 235056). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3296 of the RYR2 protein (p.Met3296Thr). |
Ambry Genetics | RCV003165586 | SCV003868911 | uncertain significance | Cardiovascular phenotype | 2022-12-09 | criteria provided, single submitter | clinical testing | The p.M3296T variant (also known as c.9887T>C), located in coding exon 68 of the RYR2 gene, results from a T to C substitution at nucleotide position 9887. The methionine at codon 3296 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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. |
Gene |
RCV003441805 | SCV004170120 | uncertain significance | not provided | 2023-10-23 | criteria provided, single submitter | clinical testing | 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; Has not been previously published as pathogenic or benign to our knowledge; Not 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: 19926015) |
Color Diagnostics, |
RCV003532063 | SCV004360750 | uncertain significance | Cardiomyopathy | 2022-10-18 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with threonine at codon 3296 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 cardiovascular disorders in the literature. This variant has not been identified 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. |
Stanford Center for Inherited Cardiovascular Disease, |
RCV000223762 | SCV000280459 | uncertain significance | not specified | 2014-11-10 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Met3296Thr (c.9887T>C) in exon 68 of the RYR2 gene (NM_001035.2) Given the large number of genes included on this panel it is expected that many individuals (including individuals who don't have inherited cardiac disease) will have at least one and possibly several rare variants found with this test. As a result it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have. The variant appears to be novel. In silico analysis with PolyPhen-2 predicts the variant to be benign while SIFT and mutationtaster predict it to be pathogenic. Unfortunately coverage at this nucleotide is poor in ExAC (mean read depth 16). The variant is not listed in ESP but I suspect there are coverage issues there as well. So unfortunately we do not have data on allele frequency in populations not selected for rare inherited heart disease. |