Submission Details

SCN10A encodes Nav1.8, a voltage-gated sodium channel with 70.4% amino acid homology to Nav1.5 (PMID:24998131). The gene displays very low expression across all tissues in the GTEx database, with the highest expression being in the testis, left ventricle and atrial appendage. SCN10A was originally classified as “disputed” for Brugada syndrome by the ClinGen Brugada Syndrome Gene Curation Expert Panel on November, 21, 2017. The genetic evidence for SCN10A variants and Brugada syndrome was derived from four main publications. These publications report genetic screening of Brugada syndrome cohorts using either small gene panels or direct sequencing of SCN10A (PMID:24998131, PMID:25691538, PMID:25842276 and PMID:27272739).

Hu et al. reviewed 150 probands with Brugada syndrome and performed targeted genetic screening for genes associated with Brugada syndrome. They identified 17 putative rare variants in SCN10A in 25 probands. However, modern allele frequency data suggests that most of these variants are too common to be a likely cause of autosomal dominant Brugada syndrome. Two variants were reported with segregation in families, but these amino acid changes (p.Gly1662Ser and p.Arg1268Gln) are reported at too high frequency in gnomAD to support an autosomal dominant mechanism (PMID:24998131).

Behr et al. sequenced seven genes associated with QRS duration in 156 SCN5A-negative patients with Brugada syndrome and identified eight putative pathogenic SCN10A variants. One putative rare pathogenic variant (p.Gly1299Asp) was observed to segregate between two affected individuals in a family. A common SNP at V1073 was found to be strongly associated with Brugada syndrome based on case-control analysis. The authors indicated that rare variants in SCN10A were unlikely to cause Brugada syndrome (PMID:25691538). Fukuyama et al. screened 240 Japanese probands suspected of having Brugada syndrome with genetic screening for variants in eight putative Brugada causal genes and found five SCN10A variants in six affected carriers. However, no genetic screening of family members was performed (PMID:25842276). Zhang et al. screened cases of sudden unexplained nocturnal death syndrome and Brugada syndrome in the Chinese Han population and identified a number of putative pathogenic variants in SCN10A without any genetic testing of family members (PMID:27272739).

Since the previous ClinGen curation in 2017, there has been no comprehensive published genetic evidence to suggest that SCN10A variants are a monogenic cause of Brugada syndrome. There is a case report of familial Brugada associated with a deletion of SCN10A and SCN5A (PMID: 29650450). A 2019 study also reported a further nine rare SCN10A variants in a cohort of 297 patients with Brugada syndrome based on sequencing of a panel of 15 putative Brugada associated genes (PMID: 31292628). Studies have explored the functional implications of rare and common SCN10A variants in experimental models (PMID: 31195250, PMID: 34312669, PMID: 33910361). GWAS analysis has also identified common variants in the SCN5A-SCN10A locus associated with variation in electrophysiological traits including Brugada syndrome (PMID: 23872634, PMID: 33948580, PMID: 33910361).

SCN10A variants may be a polygenic modifier of Brugada disease-risk, however there is no compelling evidence to suggest that the gene may cause Brugada syndrome in an autosomal dominant manner. A further limitation of the evidence presented is that SCN10A displays extremely low expression within cardiac tissue, with the SCN10A-short isoform being more abundant.

The SCN10A Brugada syndrome “disputed” classification was originally approved by the ClinGen Brugada Syndrome Gene Curation Expert Panel on November 21, 2017. This gene-disease relationship was re-evaluated on July 8, 2025, by the Hereditary Cardiovascular Disorders GCEP. Following re-evaluation and the consideration of new evidence, the gene-disease classification did not change.