Submissions for variant NM_001035.3(RYR2):c.7528A>G (p.Thr2510Ala)

gnomAD frequency: 0.00001  dbSNP: rs777279244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001099334	SCV001255781	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099335	SCV001255782	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170259	SCV001332819	uncertain significance	Cardiomyopathy	2018-03-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170259	SCV001349241	uncertain significance	Cardiomyopathy	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 25844899) and in two individuals affected with sudden unexplained death (PMID: 22677073, 29544605). This variant has been identified in 3/249098 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001099335	SCV002277968	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2510 of the RYR2 protein (p.Thr2510Ala). This variant is present in population databases (rs777279244, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 19926015, 29544605). ClinVar contains an entry for this variant (Variation ID: 875459). 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%. 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.
Ambry Genetics	RCV002393354	SCV002671954	uncertain significance	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.T2510A variant (also known as c.7528A>G), located in coding exon 50 of the RYR2 gene, results from an A to G substitution at nucleotide position 7528. The threonine at codon 2510 is replaced by alanine, an amino acid with similar properties. This variant was detected in a sudden death victim, and reportedly detected in an arrhythmia cohort, however, clinical detail was limited (Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74; Tester DJ et al. Mayo Clin. Proc., 2012 Jun;87:524-39). 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	RCV004000232	SCV004814413	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 25844899) and in two individuals affected with sudden unexplained death (PMID: 22677073, 29544605). This variant has been identified in 3/249098 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.
GeneDx	RCV004789402	SCV005401141	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Reported in individuals with sudden unexplained death or CPVT in published literature (PMID: 25844899, 22677073, 29544605); Not observed at significant frequency in large population cohorts (gnomAD); Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24025405, 19926015, 27538377, 29544605, 25844899, 22677073)