ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4096A>G (p.Thr1366Ala)

gnomAD frequency: 0.00011  dbSNP: rs369982130
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182629 SCV000234997 uncertain significance not provided 2022-05-10 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19926015)
Invitae RCV002517783 SCV000760657 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001189914 SCV001357299 uncertain significance Cardiomyopathy 2023-06-01 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 1366 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/279484 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 RCV002321721 SCV002632065 uncertain significance Cardiovascular phenotype 2020-12-29 criteria provided, single submitter clinical testing The p.T1366A variant (also known as c.4096A>G), located in coding exon 31 of the RYR2 gene, results from an A to G substitution at nucleotide position 4096. The threonine at codon 1366 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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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