Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001359392 | SCV001555261 | uncertain significance | Long QT syndrome | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1332 of the CACNA1C protein (p.Arg1332Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Timothy syndrome (PMID: 36436328). ClinVar contains an entry for this variant (Variation ID: 1051367). 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 expected to disrupt CACNA1C protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Gene |
RCV002260703 | SCV002540472 | pathogenic | not provided | 2024-04-02 | criteria provided, single submitter | clinical testing | Reported in two individuals with neurodevelopmental and psychiatric disorders; neither individual had a diagnosis of LQTS (PMID: 36436328); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36436328, 33057194, 35982159) |
| Ambry Genetics | RCV004034527 | SCV003643682 | uncertain significance | Cardiovascular phenotype | 2022-10-07 | criteria provided, single submitter | clinical testing | The c.3995G>A (p.R1332Q) alteration is located in exon 32 (coding exon 32) of the CACNA1C gene. This alteration results from a G to A substitution at nucleotide position 3995, causing the arginine (R) at amino acid position 1332 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |