Nationwide Functional Profiling Enables Clinical Reclassification of KCNH2 Variants in the French LQT2 Population

Nationwide functional profiling of 303 KCNH2 variants in the French LQT2 population reclassified 64 of 201 VUS (31.8%), including 7 pathogenic and 46 likely pathogenic calls.

• Why it matters: Most KCNH2 findings from genetic testing remain variants of uncertain significance, and translating functional channel effects into actionable clinical evidence is a major bottleneck for LQT2 interpretation.
• What they did: The study used standardized high-throughput automated patch-clamp electrophysiology plus membrane trafficking assays to test 303 KCNH2 variants (201 VUS), then integrated nine electrophysiological parameters with MeTAL and calibrated evidence using ClinGen OddsPath and likelihood-ratio methods.
• The result: Under heterozygous conditions, MeTAL predictions matched patient QTc phenotypes with 82.9% concordance for ACMG class 5 variants, and calibrated likelihood-ratio evidence graded 76.1% of VUS, enabling ACMG/AMP reclassification of 64/201.

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