ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6737C>T (p.Ser2246Leu) (rs121918597)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182746 SCV000235131 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing The S2246L pathogenic variant in the RYR2 gene has been reported previously in association with CPVT and sudden unexplained death (SUD) (Priori et al., 2001; Tester et al., 2004; Kawamura et al., 2013). Initially, S2246L was reported as occurring de novo in an 8 year-old male with a history of recurrent syncope and ventricular arrhythmias during exercise testing (Priori et al., 2001). Subsequently, S2246L was identified in two young males with SUD and one Japanese individual with CPVT (Tester et al., 2004; Kawamura et al., 2013). The S2246L pathogenic variant was not observed in the Exome Aggregation Consortium or in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S2246L variant is located at a position that is conserved across species in the central domain of the RYR2 gene, one of the three hot-spot regions of the RYR2 gene where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, functional studies show that the S2246L variant results in abnormal calcium channel function (Wehrens et al., 2003; Jiang et al., 2005; Suetomi et al., 2011).
Invitae RCV000466223 SCV000541725 pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2246 of the RYR2 protein (p.Ser2246Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 23595086, 19926015, 26114861, 16843546, 11208676). In three of these cases, including two monozygotic twins, the variant was reported to have arisen de novo (PMID: 16843546, 11208676). ClinVar contains an entry for this variant (Variation ID: 12954). Experimental studies have shown that this missense change increases calcium sensitivity and binding affinity to RYR2 ligand FKBP12.6 in vitro (PMID: 19226252, 12837242, 16239587, 18092949) and in vivo in knock-in mice (PMID: 21768539). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013820 SCV000034067 pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2002-07-02 no assertion criteria provided literature only

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