ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4692G>A (p.Met1564Ile) (rs201675951)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000143946 SCV000188826 uncertain significance Primary dilated cardiomyopathy 2014-11-27 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157455 SCV000207199 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-11-27 no assertion criteria provided clinical testing
GeneDx RCV000766716 SCV000235108 uncertain significance not provided 2014-02-10 criteria provided, single submitter clinical testing p.Met1564Ile (ATG>ATA): c.4692 G>A in exon 36 of the RYR2 gene (NM_001035.2). The M1564I variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The M1564I variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The M1564 residue is not uniformly conserved across species. In silico analysis predicts M1564I is benign to the protein structure/function. In addition, the M1564I variant is not located in any of the RYR2 mutation hot spots (Medeiros-Domingo A et al., 2009). However, the M1564I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. With the clinical and molecular information available at this time, we cannot definitively determine if M1564I is a disease-causing mutation or a rare benign variant. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to--cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in POSTMORTEM,ARVC panel(s).
Invitae RCV000796192 SCV000935695 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-08-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1564 of the RYR2 protein (p.Met1564Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs201675951, ExAC 0.03%). This variant has been reported in an individual with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 155831). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000182725 SCV000272389 uncertain significance not specified 2017-10-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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