ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14066A>G (p.Lys4689Arg)

gnomAD frequency: 0.00001  dbSNP: rs1085307711
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489104 SCV000577097 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The K4689R variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the K4689R substitution occurs at a position that is conserved in mammals, this variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp RCV002523413 SCV002287150 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-10-03 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 4689 of the RYR2 protein (p.Lys4689Arg). This variant is not present in population databases (gnomAD no frequency). 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: 426613). 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.

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