ClinVar Miner

Submissions for variant NM_001080.3(ALDH5A1):c.1474G>A (p.Val492Ile) (rs151294087)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000426165 SCV000510607 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000426165 SCV000564553 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing The V492I variant in the ALDH5A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V492I 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 V492I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V492I as a variant of uncertain significance.
Invitae RCV000634927 SCV000756299 uncertain significance Succinate-semialdehyde dehydrogenase deficiency 2018-08-25 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 492 of the ALDH5A1 protein (p.Val492Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs151294087, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALDH5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 376788). 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.
GenomeConnect, ClinGen RCV000634927 SCV000840263 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.

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