Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003037113 | SCV003439281 | pathogenic | Pyridoxine-dependent epilepsy | 2024-02-04 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 478 of the ALDH7A1 protein (p.Cys478Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ALDH7A1-related conditions (PMID: 17721876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1348T>A (p.Cys450Ser). ClinVar contains an entry for this variant (Variation ID: 2136321). 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%. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 24613284, 30043187). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003037113 | SCV005076048 | pathogenic | Pyridoxine-dependent epilepsy | 2024-04-26 | criteria provided, single submitter | clinical testing | Variant summary: ALDH7A1 c.1432T>A (p.Cys478Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes (gnomAD). c.1432T>A has been reported in the literature in at least two compound heterozygous individuals who were affected with Pyridoxine-Dependent Epilepsy and carried a pathogenic variant in trans (e.g. Salomons_2007, Bok_2012, deRooy_2018, Coughlin_2019, Tseng_2022). In addition, the publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant had about 14-20% activity when compared to the WT (e.g. Coulter-Mackie_2014, Coughlin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24613284, 17721876, 29661537, 30043187, 35782612, 22804844). ClinVar contains an entry for this variant (Variation ID: 2136321). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV003037113 | SCV005672256 | pathogenic | Pyridoxine-dependent epilepsy | 2024-05-03 | criteria provided, single submitter | clinical testing |