Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000413292 | SCV000492262 | uncertain significance | not specified | 2016-11-30 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the ALDH7A1 gene. The I459T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 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 I459T 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. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV000799588 | SCV000939259 | likely pathogenic | Pyridoxine-dependent epilepsy | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 459 of the ALDH7A1 protein (p.Ile459Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373649). 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 ALDH7A1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ile459 amino acid residue in ALDH7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20814824, 30043187; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |