Submissions for variant NM_001035.3(RYR2):c.3265C>T (p.Arg1089Cys)

dbSNP: rs879255350

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239289	SCV000296977	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2015-09-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181058	SCV001346123	uncertain significance	Cardiomyopathy	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1089 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 1/249028 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	RCV003153544	SCV001484974	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1089 of the RYR2 protein (p.Arg1089Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 252508). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR2 protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV002500840	SCV002775736	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000239289	SCV004823549	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1089 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). 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 1/249028 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	RCV004658998	SCV005158783	uncertain significance	Cardiovascular phenotype	2024-06-07	criteria provided, single submitter	clinical testing	The p.R1089C variant (also known as c.3265C>T), located in coding exon 28 of the RYR2 gene, results from a C to T substitution at nucleotide position 3265. The arginine at codon 1089 is replaced by cysteine, an amino acid with highly dissimilar 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 variant remains unclear.