A Phenotype-Enhanced Variant Classification Framework to Decrease the Burden of Variants of Uncertain Significance in Type 2 Long QT Syndrome

Background: Pathogenic/likely pathogenic variants in the KCNH2-encoded Kv11.1 potassium channel cause type 2 long QT syndrome (LQT2). Despite the updated 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNH2 variants of uncertain significance (VUS) in patients evaluated for long QT syndrome (LQTS) remains ∼30%. Previously, we developed and validated phenotype-enhanced (PE) ACMG variant adjudication for type 1 long QT syndrome. Objectives: The purpose of this study was to determine whether a PE-ACMG variant classification approach can reduce the VUS burden in patients with clinically suspected LQT2. Methods: Retrospective analysis was performed on 209 unique missense variants within KCNH2 from 2 LQTS specialty centers. Each variant was categorized based on the classification on the initial genetic test reports. Subsequently, all VUS were re-adjudicated with the use of a PE-ACMG framework that incorporates the patient's phenotype using the LQTS clinical diagnostic Schwartz score plus 2 LQT2-defining features: 1) biphasic/notches T waves; and 2) LQTS-triggered events during emotional stress or auditory stimuli. Results: In total, 69/209 (33%) unique KCNH2 variants were classified as VUS based on their initial genetic test report. Mean Schwartz score for patients with a VUS was 3.6, and 41 patients (29%) had a score over 3.5. After PE-ACMG adjudication, 31/69 variants (45%) were upgraded to pathogenic, 18 (26%) to likely pathogenic, and 11 (16%) were downgraded to benign variants. Only 9 of 69 variants (13%) remained VUS. Overall, the VUS burden decreased from 69 of 209 (33%) to 9/209 (4%; P < 0.0001). Conclusions: Phenotype-guided variant adjudication significantly decreased the VUS burden of LQT2 case–derived KCNH2 missense variants from 2 LQTS specialty centers. There is clear value in incorporating LQT2-specific phenotype/clinical data to aid in the interpretation of KCNH2 missense variants identified during LQTS genetic testing, thereby facilitating prompt initiation of LQT2-guided therapy and cascade testing of appropriate relatives.