KCNQ1 KCNH2 Mutation Severity Classifier

KCNQ1 / KCNH2 Mutation Severity Classifier: background and clinical context This classifier synthesizes information about variant type (truncating vs missense vs CNV), protein location (pore, voltage sensor, transmembrane, regulatory domains), predicted functional effect (loss-of-function, dominant-negative, gain-of-function), and clinical phenotype (QTc duration, syncope, cardiac arrest, family sudden cardiac death) to produce a weighted severity score and a pragmatic risk category. Variants that truncate the protein, affect pore or voltage-sensing domains, or produce dominant-negative effects—especially when accompanied by a prolonged QTc (>= 500 ms), syncope, or family SCD—have been associated with higher arrhythmic risk in LQTS. Functional studies, genotype–phenotype registries, and region-specific analyses of KCNQ1 and KCNH2 show that both gene- and region-specific features materially affect penetrance and event risk; therefore, classifier outputs should be integrated with ACMG pathogenicity assessment, family segregation, and—when available—experimental electrophysiology or trafficking data for final clinical decisions.