ClinVar Miner

Submissions for variant NM_001080.3(ALDH5A1):c.608C>T (p.Pro203Leu)

gnomAD frequency: 0.00001  dbSNP: rs906284769
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001885302 SCV002229776 pathogenic Succinate-semialdehyde dehydrogenase deficiency 2022-11-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro203 amino acid residue in ALDH5A1. Other variant(s) that disrupt this residue have been observed in individuals with ALDH5A1-related conditions (PMID: 26268900), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 32402538). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 1334843). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 27815844). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the ALDH5A1 protein (p.Pro203Leu).
GeneDx RCV002307765 SCV002601216 pathogenic not provided 2024-01-04 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant damages normal protein function (PMID: 32402538); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25558043, 33203024, 26268900, 34882073, 31069529, 27815844, 32402538, 37962671)
Elsea Laboratory, Baylor College of Medicine RCV001885302 SCV002819983 pathogenic Succinate-semialdehyde dehydrogenase deficiency 2021-03-08 criteria provided, single submitter curation
Neuberg Centre For Genomic Medicine, NCGM RCV001885302 SCV002820259 likely pathogenic Succinate-semialdehyde dehydrogenase deficiency criteria provided, single submitter clinical testing The missense variant p.P203L in ALDH5A1 (NM_001080.3) has been previously reported in affected patients, most recently in twins of Indian origin (Pop A et al, Pearl P et al, Attri SV et al). The p.P203L variant is observed in 2/30,592 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P203L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 203 of ALDH5A1 is conserved in all mammalian species. The nucleotide c.608 in ALDH5A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Genetic Services Laboratory, University of Chicago RCV001815110 SCV002061994 uncertain significance not specified 2018-02-21 flagged submission clinical testing

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