Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000170795 | SCV000223350 | uncertain significance | not provided | 2018-12-07 | criteria provided, single submitter | clinical testing | The I932T variant of uncertain significance in the CACNA1C gene has not been published as pathogenic or been reported as benign to our knowledge. I932T is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I932T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position where only amino acids with similar properties to isoleucine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. |
Ambry Genetics | RCV000618294 | SCV000736064 | uncertain significance | Cardiovascular phenotype | 2020-08-31 | criteria provided, single submitter | clinical testing | The p.I932T variant (also known as c.2795T>C), located in coding exon 21 of the CACNA1C gene, results from a T to C substitution at nucleotide position 2795. The isoleucine at codon 932 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV001852043 | SCV002191466 | uncertain significance | Long QT syndrome | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 932 of the CACNA1C protein (p.Ile932Thr). This variant is not present in population databases (gnomAD no frequency). 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: 190657). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |