Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522519 | SCV000619776 | uncertain significance | not provided | 2017-08-04 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the CACNA1C gene. The T330M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T330M 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity. |
| Ambry Genetics | RCV000621455 | SCV000738224 | uncertain significance | Cardiovascular phenotype | 2020-04-06 | criteria provided, single submitter | clinical testing | The p.T330M variant (also known as c.989C>T), located in coding exon 7 of the CACNA1C gene, results from a C to T substitution at nucleotide position 989. The threonine at codon 330 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001220486 | SCV001392478 | uncertain significance | Long QT syndrome | 2023-05-26 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs377345545, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 330 of the CACNA1C protein (p.Thr330Met). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. ClinVar contains an entry for this variant (Variation ID: 451121). |