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Mutations in  CACNA1C  that increase current through the Ca V 1.2 L-type Ca 2+  channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in  CACNA1C  in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on Ca V 1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of  CACNA1C  (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of Ca V 1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of Ca V 1.2. We also observed a negative shift of V 1/2  of activation and positive shift of V 1/2  of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on Ca V 1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the  CACNA1C  variant to diminish voltage-dependent inactivation of Ca V 1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of Ca V 1.2 can contribute to QT prolongation.

A CACNA1C Variant Associated with Reduced Voltage-Dependent Inactivation, Increased CaV1.2 Channel Window Current, and Arrhythmogenesis