ClinVar Genomic variation as it relates to human health

Variant summary: ALDH7A1 c.834G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Salomons_2007). The variant allele was found at a frequency of 5.6e-05 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.834G>A (also known as c.750G>A. ) has been reported in the literature in multiple individuals affected with Pyridoxine-Dependent Epilepsy (examples: Salomons_2007 and Marguet_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17721876, 27438048). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.834G>A variant (also known as p.V278V), located in coding exon 9, results from a G to A substitution at nucleotide position 834 of the ALDH7A1 gene. This nucleotide substitution does not change the amino acid at codon 278. This nucleotide position is well conserved in available vertebrate species. This alteration has been detected in the homozygous and compound heterozygous state with other ALDH7A1 variants in several individuals with diagnoses of pyridoxine-dependent epilepsy (PDE) (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8; Mercimek-Mahmutoglu S et al. Pediatrics, 2012 May;129:e1368-72; Proudfoot M et al. JIMD Rep, 2013 Mar;10:103-6; Coughlin CR et al. Mol. Genet. Metab. May;116:35-43; Yuzyuk T et al. Mol. Genet. Metab., 2016 07;118:167-72). In one study, authors isolated RNA from a homozygous individual to show that this alteration preferentially uses a cryptic donor splice site resulting in an out of frame deletion in exon 9 which leads to the p.Val250Glyfs*23 frameshift (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8). Of note, this alteration is often called p.V250V (c.750G>A) in the literature. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to create a new alternate splice donor site, but BDGP does not predict the creation of a non-native donor site, nor a deleterious effect on splicing; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This sequence change affects codon 278 of the ALDH7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALDH7A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs201948406, gnomAD 0.01%). This variant has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17721876, 19128417, 20554659, 20814824, 22529283, 23022070, 23430810, 24122892, 27438048). 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 c.750G>A. ClinVar contains an entry for this variant (Variation ID: 18002). Studies have shown that this variant results in cryptic splice site activation, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17721876). For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect, suggesting this variant leads to abnormal gene splicing (PMID: 17721876); This variant is associated with the following publications: (PMID: 23022070, 22529283, 20554659, 36065636, 19128417, 24122892, 17721876, 26026794, 27324284, 23430810, 28973083, 29852413, 24748525, 20814824, 30043187, 31589614, 35782612, 31440721, 27438048)

The ALDH7A1 c.834G>A variant is not predicted to result in an amino acid change (p.=). This variant can also be denoted as c.750G>A (p.Val250Val) using transcript NM_001201377. This variant has been commonly reported in the homozygous and compound heterozygous states in patients with pyridoxine-dependent epilepsy (e.g., Salomons et al. 2007. PubMed ID: 17721876; Bennett et al. 2009. PubMed ID: 19128417; Mills et al. 2010. PubMed ID: 20554659; Mercimek-Mahmutoglu et al. 2012. PubMed ID: 22529283). Splicing prediction programs indicate that the c.834G>A variant strengthens a cryptic splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). RNA studies from a homozygous patient and her relatives confirmed the activation of the cryptic splice site, which was found to lead to a deletion of 40 nucleotides in the ALDH7A1 mRNA and was predicted to lead to a frameshift and premature protein termination; the results of their studies indicated that this change may also lead to nonsense-mediated mRNA decay (Salomons et al. 2007. PubMed ID: 17721876). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

The 2nd most common pathogenic variant, accounting for 5.4% of pathogenic variants