Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000170812 | SCV000223367 | uncertain significance | not provided | 2013-04-22 | criteria provided, single submitter | clinical testing | p.Pro1643Ser (CCC>TCC): c.4927 C>T in exon 40 of the CACNA1C gene (NM_000719.6). The Pro1643Ser variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro1643Ser results in a non-conservative amino acid substitution of a non-polar Proline with a polar Serine at a position that is not well conserved across species. In silico analysis predicts Pro1643Ser is benign to the protein structure/function. No mutations in nearby codons have been reported in association with arrhythmia, indicating this region of the protein may be tolerant of change. Nevertheless, the Pro1643Ser variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Pro1643Ser is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). |
Invitae | RCV001852044 | SCV002266973 | uncertain significance | Long QT syndrome | 2022-03-11 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1643 of the CACNA1C protein (p.Pro1643Ser). This variant is present in population databases (rs786205764, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190674). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. |