Key result
The KCNH2:p.(Ser906Leu) variant exhibited incomplete penetrance for Long QT Syndrome type 2 and reduced heterozygous hERG current density by 60.4%, supporting its reclassification as a low penetrant likely pathogenic variant.
Why the study?
Eight index patients were identified with a new KCNH2 VUS, prompting evaluation of its biophysiological effects to enable reclassification and guide clinical decision-making.
Observational (n=28)
Yes
Absolute Event Rate: 42.8% vs 107.9%
The KCNH2:p.(Ser906Leu) variant causes a moderate loss of function and exhibits reduced penetrance, supporting its reclassification as a likely pathogenic variant for Long QT Syndrome type 2.
KCNH2-p.S906L may confer arrhythmia risk; leaves open pathogenicity classification pending clinical correlation.
Background Variants in KCNH2 , encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K + current (I Kr ), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2 :c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2 , (II) KCNH2 -p.S906L alone (homozygous, Hm) or (III) KCNH2 -p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data. Results Incomplete penetrance of LQTS2 in KCNH2 :p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 , or AKAP9 . The phenotype of carriers of KCNH2 :p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2 -p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2 -p.S906L-Hm compared to KCNH2 -WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%. Conclusion The reduced current density in the KCNH2 -p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2 :p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.
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Copier et al. (2022) conducted an observational in Long QT Syndrome type 2 (n=28). KCNH2:p.(Ser906Leu) variant vs. Wild type KCNH2 was evaluated on hERG tail current density at 40 mV (pA/pF). The KCNH2:p.(Ser906Leu) variant exhibited incomplete penetrance for Long QT Syndrome type 2 and reduced heterozygous hERG current density by 60.4%, supporting its reclassification as a low penetrant likely pathogenic variant.
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