ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His) (rs1057517711)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584800 SCV000692528 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-04-19 criteria provided, single submitter research The CACNA1C Arg518His variant had been identified in a few probands with mixed phenotypes of Long QT, congenital heart defects and HCM (Boczek NJ, et al., 2015; Genedx, personal communication) and has been found to segregate in 2 families with varying phenotypes (Boczek NJ, et al., 2015). In vitro functional analysis using whole cell patch clamping confirmed the loss of current density and inactivation in combination with increased window and later voltage gated calcium channel current (Boczek NJ, et al., 2015), however this study may not necessarily reflect biological function and future studies will be useful to validate these findings. The variant is present a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.00003230, http://exac.broadinstitute.org/). We identified this variant in a patient diagnosed with HCM in their adoloscence, the patient had a known family history of disease and a prolonged QT was noted when the patient was in his 40s. The probands affected son also harbours this variant. He was diagnosed with HCM at 2 months. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to have deleterious effect. In summary, based on a few proband's reported with similar phenotypes, strong segregation data, rarity in general population databases, as well supportive in silico tools in combination with a functional study suggestive of an affect on protein function, we classify the CACNA1C Arg518His as "likely pathogenic".
GeneDx RCV000412828 SCV000490448 pathogenic not provided 2016-09-19 criteria provided, single submitter clinical testing The R518H pathogenic variant has previously been reported in one proband with LQTS (Boczek et al., 2015). In addition, this variant has been observed in other unrelated individuals referred for LQTS genetic testing at GeneDx, and was found to segregate with disease in at least one affected relative. The R518H variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Another pathogenic missense variant affecting the same residue (R518C) has been reported in the Human Gene Mutation Database in association with LQTS and hypertrophic cardiomyopathy (HCM) (Stenson et al., 2014). Although the R518H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, whole cell patch clamp studies revealed R518H results in loss of current density and inactivation in combination with increased window and late channel current (Boczek et al., 2015). In summary, R518H in the CACNA1C gene is interpreted as a pathogenic variant.
Invitae RCV000631664 SCV000752747 uncertain significance Long QT syndrome 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 518 of the CACNA1C protein (p.Arg518His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 26253506). ClinVar contains an entry for this variant (Variation ID: 372313). Experimental studies have shown that this missense change reduces the current density of the CACNA1C channel (PMID: 26253506). A different missense substitution at this codon (p.Arg518Cys) has been determined to be pathogenic (PMID: 26253506, Invitae). This suggests that the arginine residue is critical for CACNA1C protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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