ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.538G>A (p.Ala180Thr) (rs786205769)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170828 SCV000223383 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing The Ala180Thr variant in the CACNA1C gene has not been reported previously as a disease-causing mutation nor is it known to be a common benign polymorphism, to our knowledge. Ala180Thr represents a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue in an evolutionarily highly conserved position of the protein. In addition, Ala180Thr was not observed in up to 600 chromosomes of Caucasian and African American individuals tested at GeneDx, indicating it is not a common benign polymorphism in these populations. Thus, with the clinical and molecular information available at this time, we cannot conclude unequivocally that Ala180Thr is a disease-causing mutation associated with arrhythmia. The variant is found in BRUGADA panel(s).
Invitae RCV000691272 SCV000819024 uncertain significance Long QT syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 180 of the CACNA1C protein (p.Ala180Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190690). 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: "Possibly 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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