Calibrated Functional Data Decreases Clinical Uncertainty for KCNH2-related Long QT Syndrome

Rare missense variants are often classified as variants of uncertain significance (VUS) due to insufficient evidence for classification. These ambiguous findings create anxiety and frequently lead to inappropriate workup, colloquially referred to as the diagnostic odyssey. Well-validated high-throughput experimental data have the potential to significantly reduce the number of VUS identified by clinical genetic testing, though the extent of this reduction and the optimal strategies to achieve it remain unclear.1