ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1276A>G (p.Thr426Ala) (rs150305320)

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Total submissions: 2
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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 uncertain significance Pyridoxine-dependent epilepsy 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 426 of the ALDH7A1 protein (p.Thr426Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs150305320, ExAC 0.08%). This variant has not been reported in the literature in individuals with ALDH7A1-related disease. ClinVar contains an entry for this variant (Variation ID: 388119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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