ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2578C>G (p.Arg860Gly) (rs758786846)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170841 SCV000223396 pathogenic not provided 2018-01-03 criteria provided, single submitter clinical testing A R860G pathogenic variant was identified in the CACNA1C gene. This variant has been reported in a 30-year-old male with a diagnosis of LQTS but no extracardiac findings (Wemhöner et al., 2015). In functional studies, R860G was shown to be normally expressed at the plasma membrane in Hek293 cells but displayed a positive shift in voltage-dependent inactivation resulting in a gain-of-function in Xenopus oocytes. Additionally, computational studies suggested R860G leads to prolongation of the action potential duration (Wemhöner et al., 2015). The R860G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, the R860G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (P857L, P857R, R858H) have been identified at GeneDx and/or reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, Boles et al. (2017) identified a variant in the same residue (R860Q) in an individual with aborted cardiac arrest and performed X-ray crystallography that showed the R860Q variant is located near residue N755 and aids in creating a hydrogen-bond interaction, leading to an over-stabilized structure of the domain causing voltage augmentation.

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