Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000444022 | SCV000522448 | uncertain significance | not provided | 2017-11-15 | criteria provided, single submitter | clinical testing | The Y782S variant in the ALDH18A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y782S variant was not observed in approximately XXXX 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 Y782S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (T782C, H784Y) have been reported in the Human Gene Mutation Database in association with ALDH18A-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y782S as a variant of uncertain significance. |
| Institute Of Human Genetics Munich, |
RCV000995483 | SCV001149671 | likely pathogenic | ALDH18A1-related de Barsy syndrome | 2018-10-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003766249 | SCV004610803 | uncertain significance | Cutis laxa, autosomal dominant 3; Autosomal dominant spastic paraplegia type 9; de Barsy syndrome | 2022-11-27 | 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) 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 ALDH18A1 protein function. ClinVar contains an entry for this variant (Variation ID: 382498). This variant has not been reported in the literature in individuals affected with ALDH18A1-related conditions. This variant is present in population databases (rs774047299, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 782 of the ALDH18A1 protein (p.Tyr782Ser). |