Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000170837 | SCV000223392 | uncertain significance | not provided | 2017-03-07 | criteria provided, single submitter | clinical testing | p.Val474Phe (GTC>TTC): c.1420 G>T in exon 10 of the CACNA1C gene (NM_000719.6). The V474F variant has not been published as a mutation or as a benign polymorphism to our knowledge. The V474F variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, this substitution occurs at a position that is completely conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V474F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, no missense mutations in nearby residues have been reported in association with disease, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). |
| Baylor Genetics | RCV003147376 | SCV003835883 | uncertain significance | Long qt syndrome 8 | 2022-11-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003647747 | SCV004510480 | uncertain significance | Long QT syndrome | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 474 of the CACNA1C protein (p.Val474Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 190698). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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. |