ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1276A>G (p.Thr426Ala)

gnomAD frequency: 0.00019  dbSNP: rs150305320
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417460 SCV000530343 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing The T426A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense variant at the same position (T426P) has been reported previously (using alternative nomenclature of T398P) in siblings with pyridoxine-dependent epilepsy who have a second ALDH7A1 variant on the other chromosome (Mills et al., 2010). The T426A variant is observed in 13/24024 (0.05%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016). The T426A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with ALDH7A1-related disorders (Stenson et al., 2014). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000814956 SCV000955395 likely benign Pyridoxine-dependent epilepsy 2023-11-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV000814956 SCV001529631 uncertain significance Pyridoxine-dependent epilepsy 2018-07-30 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics RCV002374690 SCV002684862 uncertain significance Inborn genetic diseases 2017-10-27 criteria provided, single submitter clinical testing The p.T426A variant (also known as c.1276A>G), located in coding exon 14 of the ALDH7A1 gene, results from an A to G substitution at nucleotide position 1276. The threonine at codon 426 is replaced by alanine, an amino acid with similar properties. In one study, a different alteration located at the same position, p.T426P (which is referred to as p.T398P in the paper), was detected in three siblings with pyridoxine-dependent epilepsy (PDE) who also carried ALDH7A1 p.A129P on their opposite chromosome(s) (in trans) (Mills PB et al. Brain, 2010 Jul;133:2148-59). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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