Submissions for variant NM_001035.3(RYR2):c.3023C>T (p.Ala1008Val)

dbSNP: rs1232224119

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198072	SCV001368857	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001198072	SCV002222576	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 1008 of the RYR2 protein (p.Ala1008Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). 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: 931489). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
Ambry Genetics	RCV004033475	SCV005037120	uncertain significance	Cardiovascular phenotype	2024-03-05	criteria provided, single submitter	clinical testing	The p.A1008V variant (also known as c.3023C>T), located in coding exon 26 of the RYR2 gene, results from a C to T substitution at nucleotide position 3023. The alanine at codon 1008 is replaced by valine, 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004803558	SCV005426674	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1008 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 1/31398 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.