Submissions for variant NM_001035.3(RYR2):c.3460C>T (p.Arg1154Cys)

gnomAD frequency: 0.00003  dbSNP: rs765617616

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV005054288	SCV001156269	uncertain significance	Dilated cardiomyopathy 1C	2018-10-16	criteria provided, single submitter	research	The RYR2 Arg1154Cys variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000014. We identified this variant in a HCM proband with a family history of disease and SCD. Computational tools SIFT, MutationTaster, and PolyPhen2 predict this variant to have a deleterious effect. In summary, based on the limited information and rarity in the general population, we classify RYR2 Arg1154Cys as a variant of "uncertain significance".
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549128	SCV003253439	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-06-02	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 1154 of the RYR2 protein (p.Arg1154Cys). This variant is present in population databases (rs765617616, 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: 810737). 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 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.
GeneDx	RCV003313163	SCV004012702	uncertain significance	not provided	2023-01-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
All of Us Research Program, National Institutes of Health	RCV004004465	SCV004833170	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1154 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 RYR2-related disorders in the literature. This variant has been identified in 3/280428 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003313163	SCV005198101	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing