Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

SCN4B – Long QT Syndrome

SCN4B encodes the β4 subunit of the cardiac sodium channel (NaV1.5), and autosomal dominant variants have been reported in Long QT syndrome (PMID:29501670). However, rare SCN4B variants are frequently identified in population and clinical WES cohorts (38.3% of 7244 probands) without accompanying QT prolongation or clinical suspicion (PMID:29501670). A multicentered evidence-based reappraisal classified SCN4B among genes with limited or disputed evidence for typical LQTS causality (PMID:31983240), and no familial segregation data support pathogenicity.

Functional studies of β4-subunit variants (e.g., p.Ile80Thr) show modest Nav1.5 gating alterations but fail to reproduce LQTS phenotypes, and in Brugada-focused analyses these variants were considered risk factors rather than primary causes (PMID:34476357, PMID:26179811). A variant associated with ventricular tachycardia (p.Gly8Ser) further illustrates a lack of LQTS specificity (PMID:31020414). Overall, current genetic and experimental data support a ClinGen classification of Limited clinical validity for SCN4B in Long QT syndrome. SCN4B variant interpretation should be cautious, and the gene should not be included in diagnostic panels for typical LQTS absent additional evidence.

References

  • Heart rhythm • 2018 • Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise. PMID:29501670
  • Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240
  • Bioelectricity • 2020 • Biophysical Investigation of Sodium Channel Interaction with β-Subunit Variants Associated with Arrhythmias PMID:34476357
  • Circulation journal • 2015 • Contribution of Cardiac Sodium Channel β-Subunit Variants to Brugada Syndrome PMID:26179811
  • Molecular genetics and genomics : MGG • 2019 • Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia PMID:31020414

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Frequent incidental SCN4B variants in 38.3% of WES probands without phenotype ([PMID:29501670]); no segregation or case enrichment; curated as limited evidence ([PMID:31983240])

Genetic Evidence

Limited

Case-series show high background frequency of rare SCN4B variants without clinical LQTS enrichment ([PMID:29501670]); no familial segregation

Functional Evidence

Limited

SCN4B I80T and other variants alter Nav1.5 gating modestly ([PMID:34476357], [PMID:26179811]) but lack disease-specific functional correlation