ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1693G>A (p.Ala565Thr) (rs777945001)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170781 SCV000223336 uncertain significance not provided 2012-04-21 criteria provided, single submitter clinical testing p.Ala565Thr (GCC>ACC): c.1693 G>A in exon 13 of the CACNA1C gene (NM_000719.6). The Ala565Thr variant in the CACNA1C gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ala565Thr results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue at a position that is highly conserved throughout evolution. Additionally, the NHLBI ESP Exome Variant Server reports Ala565Thr was not observed in approximately 5,000 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, indicating 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 if the Ala565Thr variant in the CACNA1C gene is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000554639 SCV000627510 uncertain significance Long QT syndrome 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 565 of the CACNA1C protein (p.Ala565Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs777945001, ExAC 0.05%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190643). 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: "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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.