Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001229896 | SCV001402358 | uncertain significance | Long QT syndrome | 2022-05-07 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 46 of the CACNA1C protein (p.Pro46Leu). 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: 956992). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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. |
| New York Genome Center | RCV003336350 | SCV004046604 | uncertain significance | Timothy syndrome; Long qt syndrome 8; Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures | 2022-11-18 | criteria provided, single submitter | clinical testing | The c.137C>T, p.(Pro46Leu) variant identified in the CACNA1C gene substitutes a well conserved Proline for Leucine at amino acid 46/2187 (exon 2/49). This variant is found with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) with highest allele frequency of 1.0e-5 (0 homozygotes, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be pathogenic to the function of the canonical transcript (REVEL=0.75). The c.137C>T variant in CACNA1C has been reported in ClinVar as a Variant of Uncertain Significance (VarID:956992) and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the c.137C>T, p.(Pro46Leu) variant identified in the CACNA1C gene is reported as a Variant of Uncertain Significance. |