ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.70C>T (p.Arg24Cys) (rs773211348)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170813 SCV000223368 uncertain significance not provided 2012-12-31 criteria provided, single submitter clinical testing p.Arg24Cys (CGC>TGC): c.70 C>T in exon 2 of the CACNA1C gene (NM_000719.6). The Arg24Cys variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg24Cys results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a position that is conserved across species. In silico analysis predicts Arg24Cys is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Arg24Cys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS. With the clinical and molecular information available at this time, we cannot definitively determine if Arg24Cys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000473429 SCV000553018 uncertain significance Long QT syndrome 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 24 of the CACNA1C protein (p.Arg24Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs773211348, ExAC 0.005%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190675). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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