ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9138G>A (p.Met3046Ile)

gnomAD frequency: 0.00001  dbSNP: rs867521152
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002537381 SCV000953197 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2021-04-23 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 3046 of the RYR2 protein (p.Met3046Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine.
Color Diagnostics, LLC DBA Color Health RCV001190033 SCV001357444 uncertain significance Cardiomyopathy 2022-12-09 criteria provided, single submitter clinical testing This missense variant replaces methionine with isoleucine at codon 3046 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 cardiovascular disorders in the literature. This variant has not been identified 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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