Submissions for variant NM_001035.3(RYR2):c.7201C>T (p.Arg2401Cys)

gnomAD frequency: 0.00004  dbSNP: rs1321283106

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002559021	SCV002264753	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-16	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 2401 of the RYR2 protein (p.Arg2401Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of autosomal dominant RYR2-related conditions (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 922324). 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) indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg2401 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15749201, 20851825, 28100344). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002375073	SCV002670180	uncertain significance	Cardiovascular phenotype	2018-12-27	criteria provided, single submitter	clinical testing	The p.R2401C variant (also known as c.7201C>T), located in coding exon 47 of the RYR2 gene, results from a C to T substitution at nucleotide position 7201. The arginine at codon 2401 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position has been reported as located in the FKBP12 binding region, and other alterations affecting this amino acid (p.R2401H and p.R2401L) have been previously reported in association with catecholaminergic polymorphic ventricular tachycardia or sudden death (Aizawa Y et al. Int J Cardiol. 2005;99:343-5; Creighton W et al. J Mol Diagn. 2006;8:62-7). 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.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796369	SCV005417793	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PP2+PM5