Submissions for variant NM_001035.3(RYR2):c.6737C>T (p.Ser2246Leu)

dbSNP: rs121918597

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182746	SCV000235131	pathogenic	not provided	2021-10-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect by causing abnormal channel function (Wehrens et al., 2003; Jiang et al., 2005; Suetomi et al., 2011); 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); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 12954; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27114410, 18092949, 16843546, 30403697, 31112425, 30640888, 19226252, 12837242, 21768539, 11208676, 15544015, 24025405, 19926015, 26114861, 12919952, 29427818, 28202948, 12093772, 29434162, 29453248, 29453246, 30975432, 30302938, 31995186, 23595086, 16239587, 26582918)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013820	SCV000541725	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2246 of the RYR2 protein (p.Ser2246Leu). 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 (PMID: 11208676, 16843546, 19926015, 23595086, 26114861). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12954). 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%. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12837242, 16239587, 18092949, 19226252, 21768539). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798004	SCV002042914	pathogenic	Cardiomyopathy	2020-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298032	SCV003997087	pathogenic	Cardiovascular phenotype	2023-05-04	criteria provided, single submitter	clinical testing	The p.S2246L pathogenic mutation (also known as c.6737C>T), located in coding exon 44 of the RYR2 gene, results from a C to T substitution at nucleotide position 6737. The serine at codon 2246 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been reported in several unrelated individuals reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), features of CPVT, or sudden arrest/death, including several cases in whom this mutation occurred de novo (Priori SG et al. Circulation, 2001 Jan;103:196-2001; Priori SG et al. Circulation, 2002 Jul;106:69-74; Aizawa Y et al. Int J Cardiol, 2007 Mar;116:263-5; Ohno S et al. PLoS One, 2015 Jun;10:e0131517; Halvorsen M et al. Proc Natl Acad Sci U S A, 2021 Dec;118; Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65; Song JS et al. J Hum Genet, 2017 Jun;62:615-620; Roston TM et al. PLoS One, 2018 Nov;13:e0205925; Kawamura M et al. Circ J, 2013 Apr;77:1705-13; Chiu SN et al. Arch Dis Child, 2022 Jan;107:41-46; Eitoku T et al. HeartRhythm Case Rep, 2023 Mar;9:152-155). In vitro studies indicate this variant impacts protein function by way of increased calcium sensitivity (Wehrens XH et al. Cell, 2003 Jun;113:829-40; Jones PP et al. Biochem J, 2008 May;412:171-8). Furthermore, a knock-in mouse model expressing this variant recapitulated CPVT phenotype (Suetomi T et al. Circulation, 2011 Aug;124:682-94). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000013820	SCV000034067	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2002-07-02	no assertion criteria provided	literature only