Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483436 | SCV000569779 | likely pathogenic | not provided | 2016-03-24 | criteria provided, single submitter | clinical testing | The G1018E variant in the CACNA1F gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G1018E 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 where amino acids with similar properties to Glycine are tolerated across species; however, the G1018E variant results in a replacement of a polar, uncharged Glycine with a larger, acidic Glutamic Acid residue. In silico analysis predicts this variant is probably damaging to the protein structure/function, and protein modeling studies suggest that the substitution of Glycine-1018 with a larger amino acid disrupts calcium channel structure and function (Stockner and Koschak, 2015). A missense variant in the same residue (G1018R) has been reported in the Human Gene Mutation Database in association with congenital stationary night blindness (Stenson et al., 2014), supporting the functional importance of this residue of the protein. The G1018E variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000483436 | SCV004448900 | uncertain significance | not provided | 2023-07-21 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 CACNA1F protein function. ClinVar contains an entry for this variant (Variation ID: 420802). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1018 of the CACNA1F protein (p.Gly1018Glu). This variant disrupts the p.Gly1018 amino acid residue in CACNA1F. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12111638, 17949918, 19578023, 23714322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |