ClinVar Genomic variation as it relates to human health

A Homozygote Missense variant c.1292C>T in Exon 14 of the ALDH7A1 gene that results in the amino acid substitution p.Pro431Leu was identified. The observed variant has a minor allele frequency of 0.00003 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 870697]. The observed variation has previously been reported for Pyridoxine-dependent epilepsy by van Karnebeek, Clara DM, et al., 2016. For these reasons this variant has been classified as Likely Pathogenic.

This sequence change replaces proline with leucine at codon 431 of the ALDH7A1 protein (p.Pro431Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs151107837, ExAC 0.005%). This missense change has been observed in individual(s) with pyridoxine dependent seizure disorder (PMID: 17433748, 19142996, 26995068). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 870697). 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. For these reasons, this variant has been classified as Pathogenic.

The c.1292C>T (p.P431L) alteration is located in exon 14 (coding exon 14) of the ALDH7A1 gene. This alteration results from a C to T substitution at nucleotide position 1292, causing the proline (P) at amino acid position 431 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the ALDH7A1 c.1292C>T alteration was observed in <0.01% (8/251198) of total alleles studied, with a frequency of 0.01% (3/30604) in the South Asian subpopulation. This variant has been reported in the homozygous or compound heterozygous state in several individuals with pyridoxine-dependent epilepsy (Kanno, 2007; Coughlin, 2019). This amino acid position is highly conserved in available vertebrate species. The p.P431L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.