Submissions for variant NM_001035.3(RYR2):c.9094T>G (p.Cys3032Gly)

gnomAD frequency: 0.00002  dbSNP: rs193007458

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002534468	SCV000835859	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 3032 of the RYR2 protein (p.Cys3032Gly). This variant is present in population databases (rs193007458, gnomAD 0.004%). 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: 582661). 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.
Color Diagnostics, LLC DBA Color Health	RCV001186492	SCV001352932	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This variant is located in 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 not been identified 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	RCV001577590	SCV001804993	uncertain significance	not provided	2022-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); Has not been previously published as pathogenic or benign to our knowledge
AiLife Diagnostics, AiLife Diagnostics	RCV001577590	SCV002503068	uncertain significance	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002442538	SCV002683098	uncertain significance	Cardiovascular phenotype	2023-09-05	criteria provided, single submitter	clinical testing	The p.C3032G variant (also known as c.9094T>G), located in coding exon 64 of the RYR2 gene, results from a T to G substitution at nucleotide position 9094. The cysteine at codon 3032 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is highly 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.