ClinVar

Description

The homozygous p.Glu427Gln variant in ALDH7A1 was identified by our study in 1 individual with pyridoxine-dependent epilepsy. The variant has been reported in at least 10 individuals of European and unknown ethnicity with pyridoxine-dependent epilepsy (PMID: 16491085, 19128417), and has been identified in 0.06% (79/129032) of European non-Finnish, 0.02% (4/19918) of East Asian, and 0.01% (4/35418) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121912707). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 17994) as pathogenic by multiple submitters and as likely pathogenic by UCLA Clinical Genomics Center. In vitro functional studies provide some evidence that the p.Glu427Gln variant may impact protein function (PMID: 22784480, 16491085). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 5 affected homozygotes, and in combination with 2 reported pathogenic variants, and in at least 10 individuals with pyridoxine-dependent epilepsy increases the likelihood that the p.Glu427Gln variant is pathogenic (VariationID: 17995, 204852; PMID: 16491085, 19128417). The p.Glu427Gln variant is located in a region of ALDH7A1 that is essential to protein folding and stability, suggesting that this variant is in a mutational hotspot and slightly supports pathogenicity (PMID: 16491085, 31652343). One additional likely pathogenic variants, resulting in a different amino acid change at the same position (p.Glu427Gly), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 19128417). In summary, the p.Glu427Gln variant is pathogenic based off of our findings of multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM3_strong, PM5_supporting, PM1, PS3_moderate, PP3 (Richards 2015).