Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588776 | SCV000697631 | uncertain significance | not provided | 2017-05-30 | criteria provided, single submitter | clinical testing | Variant summary: The RYR2 c.836C>T (p.Thr279Met) variant involves the alteration of a conserved nucleotide, is located in MIR motif (InterPro, UniProt) and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 1/119600 control chromosomes from ExAC at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055). The variant of interest has not, to our knowledge, been reported in affected individuals with cardiac phenotypes via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. In COSMIC, this variant is reported as somatic variant in one carcinoma sample from large intestine. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
| Invitae | RCV002530919 | SCV000815946 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-04-25 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 279 of the RYR2 protein (p.Thr279Met). This variant is present in population databases (rs754312807, gnomAD 0.004%). 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: 496097). 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 not expected to disrupt RYR2 protein function. 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, |
RCV001178830 | SCV001343374 | uncertain significance | Cardiomyopathy | 2023-10-19 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 279 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with unspecified arrhythmia (PMID: 30847666). This variant has been identified in 3/249052 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. |
| Ambry Genetics | RCV003159996 | SCV003858423 | uncertain significance | Cardiovascular phenotype | 2023-02-08 | criteria provided, single submitter | clinical testing | The p.T279M variant (also known as c.836C>T), located in coding exon 11 of the RYR2 gene, results from a C to T substitution at nucleotide position 836. The threonine at codon 279 is replaced by methionine, an amino acid with similar properties. This variant was detected in an 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). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |