Submissions for variant NM_001035.3(RYR2):c.1240C>T (p.Arg414Cys)

gnomAD frequency: 0.00001  dbSNP: rs764698152

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182678	SCV000235057	uncertain significance	not provided	2016-12-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RYR2 gene.The R414C variant was previously published in a 16-year-old female who died while swimming competitively, and it was absent from 400 controls (Creighton et al., 2006). The R414C variant was subsequently reported in a 10-year-old boy who was experiencing ventricular fibrillation during a swimming race (Moray et al., 2011). The R414C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R414C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The R414C variant is 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 predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to arginine are tolerated across species. While another variant at this same residue (R414L) and variants in nearby residues (S406L, R407S, S413T, T415R, I419F) have been reported in HGMD in association with CPVT (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Finally, the R414C variant is classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000230388.1; Landrum et al., 2016).
Ambry Genetics	RCV000251690	SCV000320388	uncertain significance	Cardiovascular phenotype	2017-07-21	criteria provided, single submitter	clinical testing	The p.R414C variant (also known as c.1240C>T), located in coding exon 14 of the RYR2 gene, results from a C to T substitution at nucleotide position 1240. The arginine at codon 414 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in a ten year old boy with ventricular fibrillation during swimming, as well as in the boy's reportedly healthy mother (Moray A et al. Heart Lung Circ, 2011 Nov;20:731-3). This alteration was also reported in an individual who experienced sudden cardiac death at age sixteen while swimming (Tester DJ et al. Mayo Clin Proc 2005;80(5):596-600; Creighton et al. J Mol Diagn. 2006;8(1):62-7). Another alteration affecting this amino acid (p.R414L) has also been reported in association with drowning (Choi G. Circulation. 2004;110(15):2119-24). This amino acid position is well 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.
Invitae	RCV002516868	SCV000760654	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-25	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 414 of the RYR2 protein (p.Arg414Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant RYR2-related conditions (PMID: 15887426, 21478052; Invitae). ClinVar contains an entry for this variant (Variation ID: 201212). 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%. Experimental studies have shown that this missense change does not substantially affect RYR2 function (PMID: 23152493). This variant disrupts the p.Arg414 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15466642, 16188589), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000182678	SCV001147748	likely pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186513	SCV001352962	uncertain significance	Cardiomyopathy	2020-01-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 414 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. An experimental study has shown that this variant does not affect the calcium sensitivity of RYR2 channels (PMID: 23152493). This variant has been reported in two unrelated individuals affected with sudden cardiac death (PMID: 15887426, 21478052). This variant has also been reported in a healthy parent of one of the two probands, who had no history of cardiac arrhythmias (PMID: 21478052). 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.
Clinical Genetics, Academic Medical Center	RCV000182678	SCV001918603	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000182678	SCV001963566	uncertain significance	not provided		no assertion criteria provided	clinical testing