Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Biesecker Lab/Clinical Genomics Section, |
RCV000171678 | SCV000055285 | uncertain significance | not provided | 2013-06-24 | criteria provided, single submitter | research | |
Gene |
RCV000171678 | SCV000235124 | uncertain significance | not provided | 2023-07-13 | criteria provided, single submitter | clinical testing | Reported in association with atrial fibrillation (Maltese et al., 2019) and LVNC (Mazzarotto et al., 2021); Also reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 23861362, 32508047, 19926015, 31539150, 33500567) |
Laboratory for Molecular Medicine, |
RCV000212981 | SCV000272395 | uncertain significance | not specified | 2016-02-10 | criteria provided, single submitter | clinical testing | The p.Met1975Val variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66168 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s200318013). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Met1975Val variant is uncertain. |
Invitae | RCV002515249 | SCV001006346 | likely benign | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-12-04 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV001170254 | SCV001332814 | likely benign | Cardiomyopathy | 2017-11-13 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001170254 | SCV001355401 | likely benign | Cardiomyopathy | 2023-03-21 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256774 | SCV001433218 | uncertain significance | Conduction disorder of the heart | 2019-12-16 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002354428 | SCV002648160 | uncertain significance | Cardiovascular phenotype | 2022-01-13 | criteria provided, single submitter | clinical testing | The p.M1975V variant (also known as c.5923A>G), located in coding exon 39 of the RYR2 gene, results from an A to G substitution at nucleotide position 5923. The methionine at codon 1975 is replaced by valine, an amino acid with highly similar properties. This variant was detected in a proband with atrial fibrillation; however, it co-occurred with variants in other arrhythmia-related genes, one of which showed segregation with disease in the family (Maltese PE, et al. Eur Rev Med Pharmacol Sci, 2019; 23:7582-7598). This alteration was also reported in an atrioventricular nodal reentry tachycardia cohort and as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Luo R et al. Clin Transl Med, 2020 Jan;10:238-257). This amino acid position is highly 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000212981 | SCV002766113 | likely benign | not specified | 2022-11-07 | criteria provided, single submitter | clinical testing | Variant summary: RYR2 c.5923A>G (p.Met1975Val) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247224 control chromosomes. The observed variant frequency is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), suggesting that the variant is benign. c.5923A>G has been reported in the literature in individuals affected with atrial fibrilation in which the variant did not segregate with disease (Maltese_2019), in a patient with left ventricular noncompaction without strong evidence for causality (Mazzarotto_2020), and in healthy controls (Luo_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two classified as likely benign while four classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. |
Clinical Genetics, |
RCV000171678 | SCV001921521 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000171678 | SCV001965776 | uncertain significance | not provided | no assertion criteria provided | clinical testing |