Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000479462 | SCV000569921 | likely pathogenic | not provided | 2016-04-04 | criteria provided, single submitter | clinical testing | The M517I 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 M517I variant is a conservative amino acid substitution; however, it occurs at a position that is conserved across species, and missense variants in nearby residues have been reported in Human Gene Mutation Database in association with pyridoxine-dependent epilepsy (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be completely excluded. |
Invitae | RCV002525855 | SCV003203839 | uncertain significance | Pyridoxine-dependent epilepsy | 2023-01-02 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 420896). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 517 of the ALDH7A1 protein (p.Met517Ile). |