SCN5A was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in SCN5A, encoding the Nav1.5 sodium channel, are associated with a number of arrhythmia phenotypes including Brugada syndrome (loss of function variants) and Long QT syndrome (gain of function variants) for both of which SCN5A has previously been classified as a Definitive gene. The evidence for a role of SCN5A variants in CPVT comes from a single study in a large Finnish pedigree where the p.Ile141Val was found to segregate with a phenotype of exercise-induced polymorphic ventricular arrhythmias (LOD score = 3.56) with the effect of the variant confirmed by functional studies in HEK293 cells (Swan et al, 2014, PMID:25210054). Based on this study, SCN5A scored with limited evidence for association with CPVT. However, the clinical presentations in this family are atypical of a classical CPVT phenotype. While affected individuals presented with premature ventricular complexes and non-sustained polymorphic ventricular tachycardia after exercise in a similar manner to other CPVT patients (but also abundantly at rest in some), some also displayed atrial flutter and ectopic atrial rhythm that are not typical of CPVT. The expert panel therefore agreed to classify SCN5A as Disputed for CPVT. As patients with pathogenic SCN5A variants may present with a phenotype that can resemble some typical features of CPVT, it may be beneficial to include this gene in extended arrhythmia genetic testing panels for patients with a CPVT-like phenotype if no causative variants are found when sequencing validated CPVT genes. Any variants detected should be interpreted with caution however and in the context of the phenotypes of the patient being tested and those associated with SCN5A, in particular the phenotypes described by Swan et al. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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