Submissions for variant NM_001035.3(RYR2):c.12541G>A (p.Gly4181Arg)

gnomAD frequency: 0.00004  dbSNP: rs775477470

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592307	SCV000704527	uncertain significance	not provided	2017-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV002532446	SCV000834699	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4181 of the RYR2 protein (p.Gly4181Arg). This variant is present in population databases (rs775477470, gnomAD 0.009%). 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: 499175). 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.
Fulgent Genetics, Fulgent Genetics	RCV002476301	SCV000896302	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-07-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000592307	SCV001147778	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189668	SCV001357004	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 4181 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 cardiovascular disorders in the literature. This variant has been identified in 15/280364 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	RCV002420573	SCV002681124	uncertain significance	Cardiovascular phenotype	2021-11-24	criteria provided, single submitter	clinical testing	The p.G4181R variant (also known as c.12541G>A), located in coding exon 90 of the RYR2 gene, results from a G to A substitution at nucleotide position 12541. The glycine at codon 4181 is replaced by arginine, an amino acid with 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV002532446	SCV004024555	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-08-15	criteria provided, single submitter	clinical testing