A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome

Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing.Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 "LQT1-defining features": broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test.According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC.Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case-derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS.