ClinVar Genomic variation as it relates to human health

The ALDH7A1 c.1556G>A (p.Arg519Lys) variant is a missense variant. This variant, which is also known as c.1472G>A (p.Arg491Lys), has been reported in a homozygous state in one individual with developmental delay and seizures that were refractory to conventional anti-epileptics but responsive to pyridoxine (Jagadeesh et al. 2013). Urinary αAASA levels were elevated, consistent with αAASA dehydrogenase deficiency. Both parents, who were third cousins, were heterozygous, and the affected individual also had an older sibling of unknown genotype who suffered from intractable neonatal seizures and severe global developmental delay and who died at two years of age. The p.Arg519Lys variant is reported at a frequency of 0.000229 in the South Asian population of the Genome Aggregation Database. This variant is located in the C-terminus of the protein, which is important for oligomerization and the catalytic activity of the enzyme (Korasick et al. 2017), and multiple in silico algorithms predict this variant to have a deleterious effect. However, functional studies have not been conducted. Based on the evidence and the application of the ACMG criteria, the p.Arg519Lys variant is classified as a variant of uncertain significance for pyridoxine-dependent epilepsy.

A Heterozygous Missense variant c.1556G>A in Exon 17 of the ALDH7A1 gene that results in the amino acid substitution p.Arg519Lys was identified. The observed variant has a minor allele frequency of 0.00004/0% in gnomAD exomes and genomes, respectively. 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 Conflicting Interpretations of Pathogenicity (Variant ID: 623338). This variant, which is also known as c.1472G>A (p.Arg491Lys), has been reported in a homozygous state in one individual with developmental delay and seizures that were refractory to conventional anti-epileptics but responsive to pyridoxine (Jagadeesh et al. 2013). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

Variant summary: ALDH7A1 c.1556G>A (p.Arg519Lys) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) 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 4e-05 in 251428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (4e-05 vs 0.0018), allowing no conclusion about variant significance. c.1556G>A has been reported in the literature as a homozygous genotype in individuals affected with Pyridoxine-Dependent Epilepsy (Jagadeesh_2013, Krantz_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23925287, 34570182). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 519 of the ALDH7A1 protein (p.Arg519Lys). This variant is present in population databases (rs561343926, gnomAD 0.02%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 23925287). This variant is also known as p.Arg491Lys. ClinVar contains an entry for this variant (Variation ID: 623338). 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 80%. For these reasons, this variant has been classified as Pathogenic.