Submissions for variant NM_001182.5(ALDH7A1):c.584A>G (p.Asn195Ser)

gnomAD frequency: 0.00002  dbSNP: rs372660425

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206803	SCV000259268	pathogenic	Pyridoxine-dependent epilepsy	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 195 of the ALDH7A1 protein (p.Asn195Ser). This variant is present in population databases (rs372660425, gnomAD 0.006%). This missense change has been observed in individual(s) with pyridoxine-dependent seizures (PMID: 19128417, 20554659, 23350806, 24789515, 24848745). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 219413). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484609	SCV000565749	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing	The N195S variant in the ALDH7A1 gene has been reported previously in multiple unrelated patients with pyridoxine-dependent epilepsy who had a second ALDH7A1 variant on the opposite allele (Bennett et al., 2009; Della Mina et al., 2015; Nasr et al., 2015; Tincheva et al., 2015). Due to use of alternative nomenclature, this variant has been reported as N167S (Bennett et al., 2009; Nasr et al., 2015). The N195S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N195S variant is a conservative amino acid substitution. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (I191V, P197S, A199V) have been reported in the Human Gene Mutation Database in association with ALDH7A1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the N195S variant is considered to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206803	SCV002555613	pathogenic	Pyridoxine-dependent epilepsy	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: ALDH7A1 c.584A>G (p.Asn195Ser) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251480 control chromosomes. c.584A>G has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Pyridoxine-Dependent Epilepsy (Bennett_2009, Perez_2013, Coughlin_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was shown to result in a protein with a catalytic efficiency 110-fold lower than wild-type ALDH7A1 (Laciak_2020). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000206803	SCV004049716	pathogenic	Pyridoxine-dependent epilepsy	2023-04-11	criteria provided, single submitter	clinical testing