Functional analysis enables reclassification of SCN1A missense variants of uncertain significance in epilepsy

High-throughput automated patch-clamp testing reclassified 8/16 SCN1A missense variants in an Australian epilepsy cohort, including 6/12 VUS to likely pathogenic.

• Why it matters: Many SCN1A missense variants remain VUS, limiting accurate ACMG-based interpretation and slowing clinical decisions for epilepsy patients.
• What they did: The assay was validated with 27 true pathogenic and 25 true benign SCN1A variants, then applied to 16 missense variants from 31 individuals in 16 families, using current density and V0.5diff in a graded Bayesian framework.
• The result: Functional scores consistent with loss of function were found for all three likely pathogenic variants and for 10/16 variants overall, enabling ACMG integration that changed classifications for 50% (8/16) and supported therapeutic optimization and genetic-therapy access.

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