ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5923A>G (p.Met1975Val)

gnomAD frequency: 0.00004  dbSNP: rs200318013
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171678 SCV000055285 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx 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, Mass General Brigham Personalized 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, Children's Hospital of Eastern Ontario RCV001170254 SCV001332814 likely benign Cardiomyopathy 2017-11-13 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170254 SCV001355401 likely benign Cardiomyopathy 2023-03-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute 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, LabCorp 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, Academic Medical Center RCV000171678 SCV001921521 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000171678 SCV001965776 uncertain significance not provided no assertion criteria provided clinical testing

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