Submissions for variant NM_001035.3(RYR2):c.7159G>A (p.Ala2387Thr)

dbSNP: rs794728753

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182757	SCV000235142	pathogenic	not provided	2024-12-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19398665, 16391617, 24025405, 24136861, 19926015, 23595086, 15131021, 22221940, 31112425, 29434162, 33825858, Olubando2020, 16188589, 17052226, 26189708, 29453246, 34076677, 30847666, 28600387, 31737537, 28237968, 32553227, 35135837, 32152366)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217048	SCV000271263	likely pathogenic	Catecholaminergic polymorphic ventricular tachycardia	2015-02-17	criteria provided, single submitter	clinical testing	The p.Ala2387Thr variant in RYR2 has been reported in 4 individuals with clinica l features of CPVT (Tester 2005, Medeiros-Domingo 2009, Walsh 2014) and was iden tified by our laboratory to have probably occurred de novo in 1 adult with CPVT. It was absent from large population studies. This variant is located in the ce ntral domain of the RYR2 protein where other disease-causing variants are cluste red (Yano 2006, Walsh 2014) and another variant at this position (p.Ala2387Pro) has been identified in individuals with CPVT (Bagattin 2004, Steriotis 2012), su ggesting that a change at this position may not be tolerated. Computational pred iction tools and conservation analysis also suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, although additional studies are required to fully establ ish its clinical significance, the p.Ala2387Thr variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517795	SCV000836165	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-06-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala2387 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 15131021, 16188589, 19398665, 23595086, 28237968, 28600387), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 201276). This missense change has been observed in individuals with cardiac arrest and/or catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16188589, 19398665, 28237968, 28600387). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2387 of the RYR2 protein (p.Ala2387Thr).
AiLife Diagnostics, AiLife Diagnostics	RCV000182757	SCV002502332	likely pathogenic	not provided	2021-09-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362937	SCV002662760	likely pathogenic	Cardiovascular phenotype	2022-11-22	criteria provided, single submitter	clinical testing	The p.A2387T variant (also known as c.7159G>A), located in coding exon 47 of the RYR2 gene, results from a G to A substitution at nucleotide position 7159. The alanine at codon 2387 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in several patients reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), and has been detected in CPVT or sudden cardiac arrest cohorts with varying levels of clinical detail (Tester DJ et al. Heart Rhythm, 2005;2:1099-105; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009;54:2065-74; Hayashi M et al. Circulation, 2009;119:2426-34; Jiménez-Jáimez J. Am. J. Cardiol. 2015;116(6):894-9Mellor G. Circ Cardiovasc Genet. 2017;10(3); Kapplinger JD. Circ Genom Precis Med. 2018;11(2):e001424. Alterations affecting the same amino acid (p.A2387V, c.7160C>T and p.A2387P, c.7159G>C) have also been identified in CPVT cohorts (Bagattin A et al. Clin. Chem., 2004;50:1148-55; Haugaa KH et al. Europace, 2010;12:417-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.