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Background: Variants in  KCNH2,  encoding the human ether a-go-go (hERG) channel that 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 &gt; 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 independently by manual-, and automated calibrated patch clamp. 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) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. 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 with  KCNH2 -WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay 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.

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance