ClinVar

Description

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.