Submissions for variant NM_001035.3(RYR2):c.7529C>T (p.Thr2510Ile)

gnomAD frequency: 0.00001  dbSNP: rs748865411

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001180671	SCV001345666	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 2510 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 RYR2-related disorders in the literature. This variant has been identified in 2/280488 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223997	SCV002503021	uncertain significance	not provided	2021-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002393408	SCV002671957	uncertain significance	Cardiovascular phenotype	2021-09-19	criteria provided, single submitter	clinical testing	The p.T2510I variant (also known as c.7529C>T), located in coding exon 50 of the RYR2 gene, results from a C to T substitution at nucleotide position 7529. The threonine at codon 2510 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV004006678	SCV004822518	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-03-23	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/276976 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005057015	SCV005716721	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-03-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2510 of the RYR2 protein (p.Thr2510Ile). This variant is present in population databases (rs748865411, gnomAD 0.008%). 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: 921323). 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 expected to disrupt RYR2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.