Submission Details

SCN5A was first reported in relation to autosomal dominant congenital heart disease in 2017 (Jin et al., PMID: 28991257). Of note, variants in SCN5A are associated with a number of arrhythmia phenotypes including Brugada syndrome, dilated cardiomyopathy, and Long QT syndrome, all of which has previously been classified as Definitive. Additionally, SCN5A has been classified as Limited for arrhythmogenic right ventricular cardiomyopathy and Disputed for catecholaminergic polymorphic ventricular tachycardia and short QT syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into separate entities: congenital heart disease, dilated cardiomyopathy, familial long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome. This curation addresses SCN5A in relation to AD congenital heart disease. Two unique missense variants have been reported in two probands in three publications (PMIDs: 28991257, 32368696, 35885997). However, both of the variants had a high minor allele frequency (>0.00001) in gnomAD v4. Both probands were also reported with several variants in other genes, therefore none of the probands were scored. The gene-disease relationship is supported by high expression specifically in the human fetal heart tissue (NCBI fetal expression data, PMID: 26076956). In summary, the evidence supporting the relationship between SCN5A and autosomal dominant congenital heart diseases has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role SCN5A plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date December 9th, 2024 (SOP Version 11).