ClinVar Miner

Submissions for variant NM_001080.3(ALDH5A1):c.803G>A (p.Gly268Glu) (rs375628463)

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Total submissions: 3
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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 RCV000224315 SCV000281149 pathogenic not provided 2015-02-09 criteria provided, single submitter clinical testing
Invitae RCV000524751 SCV000632013 likely pathogenic Succinate-semialdehyde dehydrogenase deficiency 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 268 of the ALDH5A1 protein (p.Gly268Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs375628463, ExAC 0.02%). This variant has been reported in several individuals and families affected with succinic semialdehyde dehydrogenase deficiency, and it has been observed on the opposite chromosome (in trans) from pathogenic variants in affected individuals (PMID: 14635103, 11243727). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies have shown that this missense change greatly reduces SSADH enzyme activity (PMID: 14635103). In summary, this variant is a rare missense change that has been reported in affected individuals and shown to impact ALDH5A1 protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000524751 SCV000916136 pathogenic Succinate-semialdehyde dehydrogenase deficiency 2018-11-01 criteria provided, single submitter clinical testing The ALDH5A1 c.803G>A (p.Gly268Glu) missense variant, also known as the p.Gly281Glu variant, has been reported in a compound heterozygous state in five unrelated individuals with succinic semialdehyde dehydrogenase (SSADH) deficiency (Hogema et al. 2001; Akaboshi et al. 2003). The p.Gly268Glu variant was absent from 140 control chromosomes and is reported at a frequency of 0.000145 in the Latino population of the Genome Aggregation Database. HEK293 cells expressing the p.Gly268Glu variant demonstrated <1% SSADH activity compared to wild type (Akaboshi et al. 2003). Based on the evidence, the p.Gly268Glu variant is classified as pathogenic for succinic semialdehyde dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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