ClinVar Miner

Submissions for variant NM_001080.3(ALDH5A1):c.1316C>T (p.Thr439Ile) (rs139633130)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000422683 SCV000512010 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing The T439I variant in the ALDH5A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T439I variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T439I 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T439I as a variant of uncertain significance.
GenomeConnect, ClinGen RCV000709920 SCV000840262 not provided Succinate-semialdehyde dehydrogenase deficiency no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000709920 SCV000946153 uncertain significance Succinate-semialdehyde dehydrogenase deficiency 2018-07-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 439 of the ALDH5A1 protein (p.Thr439Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs139633130, ExAC 0.1%). This variant has not been reported in the literature in individuals with ALDH5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 377460). 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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