ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12826G>A (p.Val4276Met)

gnomAD frequency: 0.00001  dbSNP: rs368599791
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182646 SCV000235021 likely benign not specified 2014-04-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV002516863 SCV000760581 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2023-11-17 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 4276 of the RYR2 protein (p.Val4276Met). This variant is present in population databases (rs368599791, 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: 201184). 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 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.
Color Diagnostics, LLC DBA Color Health RCV001189915 SCV001357300 likely benign Cardiomyopathy 2019-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002381595 SCV002695168 likely benign Cardiovascular phenotype 2023-04-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.

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