Arrhythmias & electrophysiology
Automated patch clamp data improve variant classification and penetrance stratification for SCN5A –Brugada syndrome
Authors' conclusion
This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS.
Study context
- Population
- SCN5A missense and in-frame insertion/deletion variants from a large cohort of Brugada Syndrome (BrS) cases252 variants
- Participants
- 3,335 participants
- Outcome
- SCN5A variant function and reclassification
Methodological detailscalibrated high-throughput automated patch-clamp assay, cohort scale
- Calibrated high-throughput automated patch-clamp assay
- Cohort scale
Main finding
As reported in the abstract
- Functionally abnormal variants (Z ≤ −2)
- 146/252
- Severe loss-of-function (Z ≤ −4)
- 100
- Variants of uncertain significance (VUS) reclassified
- 110 of 225
- VUS reclassified to likely pathogenic
- 104
- VUS reclassified to likely benign
- 6
- Penetrance, variants with Z ≤ −6
- 24.5% (15.9%-37.7% CI)
- OR for BrS, variants with Z ≤ −6
- 501
Observational data: associations, not effects.
Original publication
Automated patch clamp data improve variant classification and penetrance stratification for SCN5A –Brugada syndrome. Eur Heart J. Published 18 November 2025. doi:10.
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