Arrhythmias & electrophysiology
A Phenotype-Enhanced Variant Classification Framework to Decrease the Burden of Variants of Uncertain Significance in Type 2 Long QT Syndrome
Authors' conclusion
Phenotype-guided variant adjudication significantly decreased the VUS burden of LQT2 case-derived KCNH2 missense variants from 2 LQTS specialty centers.
Study context
- Population
- Unique KCNH2 missense variants in patients with clinically suspected LQT2
- Participants
- 209 unique missense variants
- Exposure
- Phenotype-enhanced American College of Medical Genetics (ACMG) variant re-adjudication vs initial genetic test report classification
- Outcome
- VUS burden
Methodological details2 long QT syndrome (LQTS) specialty centers
- 2 LQTS specialty centers
Main finding
As reported in the abstract
VUS burden among unique KCNH2 missense variants
- Variants of uncertain significance (VUS) on initial genetic test reports
- 69/209 (33%)
- VUS burden overall, initial vs after PE-ACMG adjudication
- 69 of 209 (33%) to 9/209 (4%; P < 0.0001)
- VUS upgraded to pathogenic after PE-ACMG adjudication
- 31/69 variants (45%)
- VUS upgraded to likely pathogenic
- 18 (26%)
- VUS downgraded to benign
- 11 (16%)
- Variants remaining VUS
- 9 of 69 variants (13%)
Observational data: associations, not effects.
Further findings
Reclassification of the 69 initial VUS after PE-ACMG
- Upgraded to pathogenic
- 31/69 (45%)
- Upgraded to likely pathogenic
- 18 (26%)
- Downgraded to benign
- 11 (16%)
- Remained VUS
- 9 of 69 (13%)
Schwartz score in patients with a VUS
- Mean Schwartz score
- 3.6
- Score over 3.5
- 41 patients (29%)
Original publication
A Phenotype-Enhanced Variant Classification Framework to Decrease the Burden of Variants of Uncertain Significance in Type 2 Long QT Syndrome. JACC Clin Electrophysiol. Published 24 November 2025. doi:10.
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