Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000688780 | SCV000816404 | benign | Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV | 2022-12-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192701 | SCV001360993 | uncertain significance | not specified | 2019-11-21 | criteria provided, single submitter | clinical testing | Variant summary: CACNA1H c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249036 control chromosomes (gnomAD). c.2542G>A has been reported in the literature in a child with epilepsy and Autism Spectrum Disorder (Long_2019). It has also been reported in an individual affected with childhood absence epilepsy who had inherited the variant from their unaffected parent (Chen_2003). This study and another study (PMID: 17696120) following testing of multiple individuals affected with idiopathic generalized epilepsy, including childhood absence epilepsy, concluded that CACNA1H variants represented susceptibility alleles involved in the pathogenesis of a multifactorial disorder. However, no definitive conclusions could be drawn from these studies since no other genes indicated to be associated with the disorder were examined and since there was lack of segregation with disease in the majority of the families assessed. These data do not allow any conclusion about variant significance. Two functional studies were contradictory on their findings and did not allow convincing conclusions about the variant effect. Specifically, one study noted changes in activation and inactivation but not deactivation kinetics for the variant (Peloquin_2006) while the other study showed opposite results finding no alterations in activation and inactivation kinetics but small changes in the deactivation kinetics at very negative voltages (Vitko_2005). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |