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

gnomAD frequency: 0.00011  dbSNP: rs369982130

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182629	SCV000234997	uncertain significance	not provided	2024-01-30	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517783	SCV000760657	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-07	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	2024-07-25	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. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV003996730	SCV004817661	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-01-03	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.