ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2521A>G (p.Lys841Glu)

gnomAD frequency: 0.00004  dbSNP: rs563091152
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002538189 SCV000954658 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-11-30 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 841 of the RYR2 protein (p.Lys841Glu). This variant is present in population databases (rs563091152, gnomAD 0.007%). 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: 657616). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health RCV001191150 SCV001358855 uncertain significance Cardiomyopathy 2023-03-16 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 841 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/249300 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.
Ambry Genetics RCV002453846 SCV002739216 uncertain significance Cardiovascular phenotype 2022-06-08 criteria provided, single submitter clinical testing The p.K841E variant (also known as c.2521A>G), located in coding exon 22 of the RYR2 gene, results from an A to G substitution at nucleotide position 2521. The lysine at codon 841 is replaced by glutamic acid, an amino acid with similar properties. 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.

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