Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001050658 | SCV001214777 | uncertain significance | Pyridoxine-dependent epilepsy | 2022-07-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the ALDH7A1 protein (p.Gly165Val). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with folinic acid-responsive seizures (PMID: 19142996). This variant is also known as p.Gly137Val. ClinVar contains an entry for this variant (Variation ID: 847168). 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. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 19142996). 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. |
| Institute of Medical Genetics and Applied Genomics, |
RCV001268456 | SCV001447402 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001050658 | SCV002572170 | likely pathogenic | Pyridoxine-dependent epilepsy | 2022-08-02 | criteria provided, single submitter | clinical testing | Variant summary: ALDH7A1 c.494G>T (p.Gly165Val) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This variant is also known as G137V in the literature. The variant was absent in 251418 control chromosomes (gnomAD). c.494G>T has been reported in at-least one compound heterozygous individual reportedly affected with Folinic Acid Responsive Seizures (example: Gallagher_2009). This report does not provide unequivocal conclusions about association of the variant with Pyridoxine-Dependent Epilepsy. At least one publication reports experimental evidence evaluating an impact on protein function (example: Korasick_2017). In this study the variant abolished the catalytic activity and impaired protein assembly. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |