Submissions for variant NM_001182.5(ALDH7A1):c.1375A>T (p.Ile459Phe)

dbSNP: rs186558364

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186747	SCV000240314	likely pathogenic	not provided	2012-08-06	criteria provided, single submitter	clinical testing	p.Ile459Phe (ATC>TTC):c.1375 A>T in exon 15 of the ALDH7A1 gene (NM_001182.3). The Ile459Phe missense change was previously detected in a patient with pyridoxine-dependent epilepsy (PDE) and was reported as Ile431Phe due to the use of alternative nomenclature (Scharer et al., 2010). This patient was reported to be heterozygous for both Ile459Phe and a second mutation in the ALDH7A1 gene; however, no information was provided about whether parental studies were performed to confirm the mutations were on opposite alleles (in trans) in the affected individual. The Ile459Phe missense change alters a position that is conserved across species and in related proteins, and many other missense mutations have been reported at neighboring codons in association with PDE. Additionally, in silico protein modeling suggests that Ile459Phe may alter the secondary structure of the protein (Scharer et al., 2010). Therefore, Ile459Phe is a strong candidate to be a disease-causing mutation, although the possibility that it is a benign variant cannot be completely excluded based on the evidence currently available. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001227681	SCV001400050	pathogenic	Pyridoxine-dependent epilepsy	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 459 of the ALDH7A1 protein (p.Ile459Phe). This variant is present in population databases (rs186558364, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of pyridoxine-dependent epilepsy (PMID: 20814824, 30043187; Invitae). 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 p.Ile431Phe. ClinVar contains an entry for this variant (Variation ID: 204849). 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: 22784480). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001227681	SCV004050150	likely pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing