ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3295G>A (p.Asp1099Asn) (rs771549676)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170843 SCV000223398 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing The Asp1099Asn variant in the CACNA1C gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Asp1099Asn results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral, polar Asparagine at a residue that is conserved across species. Additionally, the Asp1099Asn variant was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. In silico analysis predicts Asp1099Asn is possibly damaging to the protein structure/function. However, Asp1099Asn is located in a region of the CACNA1C gene with few reported mutations, suggesting this region of the protein may be tolerant of change. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine whether the Asp1099Asn variant is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000687893 SCV000815485 uncertain significance Long QT syndrome 2019-05-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1099 of the CACNA1C protein (p.Asp1099Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs771549676, 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: 190704). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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