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.
References:
KCNQ1 variant integrative analyses and regional/functional correlations.
Predictive/functional evaluation frameworks for KCNQ1 (heterologous expression and computational models).
Clinical overview and risk stratification approaches in congenital long QT syndrome.
Classification and reporting considerations for potentially proarrhythmic genetic variants.
Recent integrative reviews and variant-risk studies in LQTS (genotype–phenotype correlation emphasis).
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