Submission Details

Variants in SCN5A have been widely reported in a collection of cardiac rhythm phenotypes with heterogenous expression including autosomal dominant long QT syndrome in 1995 (Wang et al. PMID: 7889574), Brugada syndrome in 1998 (Chen et al. PMID: 9521325), progressive familial heart block in 1999 (Schott et al. PMID: 10471492), and sick sinus syndrome in 2003 (Benson et al. PMID: 14523039). The molecular mechanism of disease is reported to be sodium channel dysfunction caused by either loss of function, gain of function, or both (PMIDs: 18451998, 30364184). Individuals with disease-causing variants in SCN5A are commonly reported with at least one cardiac rhythm phenotype that includes, but is not limited to, atrial fibrillation, sick sinus syndrome, progressive cardiac conduction disease, ventricular fibrillation, long QT syndrome, and Brugada syndrome. Individuals with pathogenic variants in SCN5A may also exhibit overlapping or mixed cardiac rhythm phenotypes and intrafamilial variability (PMID: 34245912).

Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no significant difference in inheritance pattern and found considerable interfamilial and intrafamilial variability of cardiac rhythm phenotypes. Therefore, the following disease entities have been lumped into one disease entity, termed “SCN5A-related cardiac rhythm disorder”: atrial conduction disease (MONDO:0014500), atrioventricular block (MONDO:0000465), Brugada syndrome (MONDO:0015263), familial atrial fibrillation (MONDO:0018054), familial sick sinus syndrome (MONDO:0012061), long QT syndrome 3 (MONDO:0011377), progressive familial heart block (MONDO:0019490), and ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376). In addition, the split curations for SCN5A in relation to autosomal dominant dilated cardiomyopathy, autosomal dominant arrhythmogenic right ventricular cardiomyopathy, and autosomal dominant congenital heart disease have been curated separately by other ClinGen gene curation expert panels.

Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and experimental data. Seventeen variants (thirteen missense, one in-frame insertion, two nonsense, one frameshift) that have been reported in seventeen probands in six publications (PMIDs: 10590249, 12051963, 18451998, 27566755, 27810048, 39134129) are included in this curation. Of note, missense variant SCN5A:p.E1784K (also known as E1783K) is reported as the most common variant among Brugada syndrome and long QT syndrome patients (PMIDs: 18451998, 27381756). Variants in this gene have also been shown to segregate with disease in family members. One such variant, SCN5A 1798insD, alternatively known as NM_000335.5:c.5382_5384dup (p.Tyr1794_Glu1795insAsp), has been extensively reported in a large Dutch pedigree with over 200 members of which carriers displayed clinical signs of long QT syndrome, sinus bradycardia on EEG, progressive cardiac conduction disease, nocturnal sudden death, or Brugada syndrome (PMID: 10590249). This gene-disease relationship has been studied in at least one case-control study at the single variant level, with p value = <0.0001 and confidence interval = 28-200, (p.Gln1118Ter Italian founder variant in relation to Type 1 BrS, CCD, Type 1 BrS pattern or CCD; PMID: 34245912).

This gene-disease relationship is supported by animal and cell models, expression and rescue studies. Expression data from adult and embryonic mice heart tissue showed SCN5A mRNA expression to be highly specific to the heart (PMID: 19255801). Transgenic mice recapitulate the clinical phenotype observed in human patients, while iPSC-derived cardiomyocyte cell models carrying SCN5A variants showed recapitulation of Na+ channel mutation dysfunction (PMIDs: 10590249, 22647976, 27810048). In vivo rescue of a transgenic mouse model using genomic base editing by dual-adeno-associated virus-delivered ABE showed alleviation of the long QT phenotype in homozygous and heterozygous Scn5A T1307M mice (PMID: 37965733). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.

In summary, there is definitive evidence to support the relationship between SCN5A and autosomal dominant heterogenous cardiac rhythm phenotypes including but not limited to cardiac arrhythmia, atrial fibrillation, sick sinus syndrome, ventricular fibrillation, long QT syndrome, and Brugada syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP and Sodium and Calcium Channel Arrhythmia VCEP on October 8, 2025 (SOP Version 11).