Submissions for variant NM_001035.3(RYR2):c.5170G>A (p.Glu1724Lys)

dbSNP: rs794728740

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182731	SCV000235115	pathogenic	not provided	2015-04-27	criteria provided, single submitter	clinical testing	p.Glu1724Lys (E1724K) GAG>AAG: c.5170 G>A in exon 37 of the RYR2 gene (NM_001035.2). Postma et al (2005) identified the Glu1724Lys mutation in one female patient diagnosed with CPVT in childhood and this mutation was also identified in this patient's affected daughter. The Glu1724Lys mutation was absent from 400 control alleles from individuals of Northern European ancestry (Postma et al, 2005). In addition, the Glu1724Lys mutation was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. Glu1724Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine. The closest pathogenic mutation reported in association with CPVT is Glu1837Lys (Medeiros-Domingo et al, 2009). However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic. The variant is found in CPVT panel(s).
Invitae	RCV002515328	SCV001393038	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1724 of the RYR2 protein (p.Glu1724Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16272262, 22787013, 26114861, 28237968, 29032884). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201254). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002336457	SCV002643685	likely pathogenic	Cardiovascular phenotype	2021-03-29	criteria provided, single submitter	clinical testing	The p.E1724K variant (also known as c.5170G>A), located in coding exon 37 of the RYR2 gene, results from a G to A substitution at nucleotide position 5170. The glutamic acid at codon 1724 is replaced by lysine, an amino acid with similar properties. This variant has been detected in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT), and was reported to segregate with symptoms in an additional relative in two unrelated families, one with confirmed CPVT and one with a history of syncope (Postma AV et al. J. Med. Genet., 2005 Nov;42:863-70; van der Werf C et al. J. Am. Coll. Cardiol., 2011 May;57:2244-54; Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517; Kawata H et al. Circ. J., 2016 Aug;80:1907-15). This variant was also reported to be de novo in one CPVT case; however, clinical details were limited (Broendberg AK et al. Heart, 2017 06;103:901-909). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Dept of Medical Biology, Uskudar University	RCV003318367	SCV004022026	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS2_Strong, PM2, PP2, PP3