A Phenotype-Enhanced Variant Classification Framework to Decrease the Burden of Variants of Uncertain Significance in...

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Pathogenic variants in KCNH2 cause long QT syndrome type 2 (LQT2).
• A significant number of KCNH2 variants remain of uncertain significance (VUS) despite current guidelines.
• Previous work established a phenotype-enhanced (PE) ACMG approach for LQT1 variants.

Purpose of the Study:

• To assess if a PE-ACMG framework can decrease the VUS burden in patients with suspected LQT2.
• To evaluate the utility of incorporating patient phenotype into variant classification for KCNH2.

Main Methods:

• Retrospective analysis of 209 KCNH2 missense variants from two LQTS centers.
• Re-adjudication of VUS using a PE-ACMG framework, incorporating Schwartz scores and LQT2-specific features (T-wave morphology, trigger events).

Main Results:

• Initially, 33% (69/209) of KCNH2 variants were VUS.
• After PE-ACMG adjudication, 45% of VUS were upgraded to pathogenic, 26% to likely pathogenic, and 16% downgraded to benign.
• The VUS burden decreased significantly from 33% to 4% (P < 0.0001).

Conclusions:

• Phenotype-guided variant adjudication effectively reduces the VUS burden for KCNH2 missense variants in LQT2.
• Integrating LQT2-specific clinical data improves KCNH2 variant interpretation.
• This facilitates earlier LQT2 treatment and cascade testing.