Submissions for variant NM_001035.3(RYR2):c.12700G>A (p.Ala4234Thr)

gnomAD frequency: 0.00001  dbSNP: rs773317989

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617924	SCV000737607	uncertain significance	Cardiovascular phenotype	2016-07-07	criteria provided, single submitter	clinical testing	The p.A4234T variant (also known as c.12700G>A), located in coding exon 90 of the RYR2 gene, results from a G to A substitution at nucleotide position 12700. The alanine at codon 4234 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs773317989. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6127 samples (12254 alleles) with coverage at this position. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (1/119280). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516901	SCV000760688	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4234 of the RYR2 protein (p.Ala4234Thr). This variant is present in population databases (rs773317989, gnomAD 0.002%). 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: 201341). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV000772650	SCV000905909	uncertain significance	Cardiomyopathy	2021-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 4234 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248114 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.
All of Us Research Program, National Institutes of Health	RCV003996785	SCV004818606	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 4234 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248114 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.