ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2617G>A (p.Val873Met)

gnomAD frequency: 0.00003  dbSNP: rs369248015
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001175870 SCV001339655 uncertain significance Cardiomyopathy 2022-12-07 criteria provided, single submitter clinical testing This variant is located in 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 cardiovascular disorders in the literature. This variant has been identified in 3/246074 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002559684 SCV001405413 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2025-01-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 873 of the RYR2 protein (p.Val873Met). This variant is present in population databases (rs369248015, gnomAD 0.003%). 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: 918326). 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.
Fulgent Genetics, Fulgent Genetics RCV002483944 SCV002775091 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-09-28 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000299 SCV004814920 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2024-09-23 criteria provided, single submitter clinical testing This variant is located in 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 cardiovascular disorders in the literature. This variant has been identified in 3/246074 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 RCV004032986 SCV005037118 uncertain significance Cardiovascular phenotype 2023-11-21 criteria provided, single submitter clinical testing The p.V873M variant (also known as c.2617G>A), located in coding exon 23 of the RYR2 gene, results from a G to A substitution at nucleotide position 2617. The valine at codon 873 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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