ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5671G>C (p.Ala1891Pro) (rs542914369)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000305564 SCV000329184 uncertain significance not provided 2016-01-07 criteria provided, single submitter clinical testing The A1891P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this 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, the 1000 Genomes Project reports A1891P was observed in approximately 0.1% of alleles from individuals of African background. The A1891P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the gene is not known to harbor pathogenic variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000538195 SCV000627572 uncertain significance Long QT syndrome 2018-04-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 1891 of the CACNA1C protein (p.Ala1891Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs542914369, ExAC 0.05%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 279723). 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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