ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5338C>T (p.Arg1780Cys) (rs371760034)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170826 SCV000223381 uncertain significance not provided 2014-08-12 criteria provided, single submitter clinical testing p.Arg1780Cys (CGC>TGC): c.5338 C>T in exon 42 of the CACNA1C gene (NM_000719.6). The R1780C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1780C variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1780C 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. However, this substitution occurs at a position that is not conserved across species and several mammalian species tolerate non-conservative amino acid changes at this position. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Although a missense variant in this same residue (R1780H) has been reported in association with Brugada syndrome, the patient harboring the R1780H mutation was reportedly an asymptomatic 57-year-old Japanese male with a Brugada ECG pattern discovered during the course of an annual checkup. Segregation studies could not be performed (Fukuyama et al., 2013). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000463099 SCV000553008 uncertain significance Long QT syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1780 of the CACNA1C protein (p.Arg1780Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs371760034, ExAC 0.02%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190688). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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