Key result
The novel CACNA1C L658P variant caused a profound hyperpolarizing shift in the voltage dependence of Cav1.2 channel activation by -30.4 mV, contributing to severe neurological dysfunction.
Why the study?
Mutations in CACNA1C are associated with a spectrum of disorders including Timothy syndrome, neurodevelopmental, and cardiac conditions, but novel variants require functional characterization to define their pathogenicity and phenotypic spectrum.
Case Report (n=1)
The L658P variant in CACNA1C is a pathogenic mutation that causes profound gating alterations in Cav1.2 channels, expanding the phenotypic spectrum of CACNA1C-related disorders to include severe neurological dysfunction without overt cardiac involvement.
Answers are grounded in this paper and cite their sources.
Broadens CACNA1C spectrum to include refractory epilepsy without cardiac dysfunction; leaves open causality and prevalence in neurodevelopmental cohorts.
Mutations in CACNA1C , the gene encoding Ca v 1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C , presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Ca v 1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C -related disorders.
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Stringer et al. (2025) conducted a case report in Neurodevelopmental disorder (n=1). CACNA1C L658P variant vs. Wild-type Cav1.2 channel was evaluated on Mean half-activation potential (MD -30.4 mV, p=<0.001). The novel CACNA1C L658P variant caused a profound hyperpolarizing shift in the voltage dependence of Cav1.2 channel activation by -30.4 mV, contributing to severe neurological dysfunction.
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