Submissions for variant NM_001035.3(RYR2):c.719A>G (p.His240Arg)

gnomAD frequency: 0.00003  dbSNP: rs369512347

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036787	SCV000060442	uncertain significance	not specified	2018-02-27	criteria provided, single submitter	clinical testing	The p.His240Arg variant in RYR2 has been reported in 1 Caucasian individual with sudden unexplained death and 1 Caucasian individual with arrhythmia and sudden cardiac arrest, both of whom carried additional variants of uncertain significan ce in RYR2 (Tester 2012; LMM data). This variant has also been identified in 0.0 02% (3/126662) of European chromosomes by gnomAD (http://gnomad.broadinstitute.o rg) and has been reported in ClinVar (Variation ID 43823). Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.His240 Arg variant is uncertain. ACMG/AMP Criteria applied: PM2.
GeneDx	RCV001547355	SCV001767041	uncertain significance	not provided	2024-09-16	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; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); Reported in association with CPVT and sudden unexplained death in published literature; however, at least one patient harbored additional cardiogenetic variants (PMID: 19926015, 24025405, 22677073); This variant is associated with the following publications: (PMID: 27114410, 19926015, 27538377, 24025405, 22677073, 36450727, 32152366)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513438	SCV002217390	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 240 of the RYR2 protein (p.His240Arg). This variant is present in population databases (rs369512347, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventriculartachycardia (CPVT) or long QT syndrome (LQTS) (PMID: 19926015, 27114410). This variant is also known as 6337G>A. ClinVar contains an entry for this variant (Variation ID: 43823). 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 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.
Fulgent Genetics, Fulgent Genetics	RCV002496575	SCV002781543	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-10-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996300	SCV004821985	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-05-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004668752	SCV005158782	uncertain significance	Cardiovascular phenotype	2024-03-29	criteria provided, single submitter	clinical testing	The p.H240R variant (also known as c.719A>G), located in coding exon 10 of the RYR2 gene, results from an A to G substitution at nucleotide position 719. The histidine at codon 240 is replaced by arginine, an amino acid with highly similar properties. This variant co-occurred with a second RYR2 variant in a child with sudden unexplained death on exertion (Tester DJ et al. Mayo Clin Proc, 2012 Jun;87:524-39). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.