ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9397A>G (p.Ile3133Val)

gnomAD frequency: 0.00008  dbSNP: rs1032783973
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002563183 SCV001402874 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2025-01-22 criteria provided, single submitter clinical testing
GeneDx RCV001776156 SCV002012989 uncertain significance not provided 2019-06-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009)
Color Diagnostics, LLC DBA Color Health RCV001806065 SCV002053048 uncertain significance Cardiomyopathy 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 3133 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/31396 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 RCV002375231 SCV002684966 uncertain significance Cardiovascular phenotype 2021-06-27 criteria provided, single submitter clinical testing The p.I3133V variant (also known as c.9397A>G), located in coding exon 66 of the RYR2 gene, results from an A to G substitution at nucleotide position 9397. The isoleucine at codon 3133 is replaced by valine, an amino acid with highly 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.
All of Us Research Program, National Institutes of Health RCV004004834 SCV004821564 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2023-05-31 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 3133 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/31396 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.

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