ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6158A>G (p.Lys2053Arg)

gnomAD frequency: 0.00003  dbSNP: rs771590345
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506199 SCV000605049 uncertain significance not specified 2016-11-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002527369 SCV001406724 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2053 of the RYR2 protein (p.Lys2053Arg). This variant is present in population databases (rs771590345, gnomAD 0.006%). This missense change has been observed in individual(s) with RYR2-related conditions (PMID: 37589201). ClinVar contains an entry for this variant (Variation ID: 440247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV002358392 SCV002661379 likely benign Cardiovascular phenotype 2024-12-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health RCV004003560 SCV004817182 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 2053 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who experienced sudden unexplained death in childhood, as well as in the asymptomatic mother who demonstrated a normal echocardiogram and lack of EST-induced arrhythmias (PMID: 37589201). This variant has been identified in 6/248400 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.

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