Submission Details

ALDH6A1 was first reported in relation to autosomal recessive methylmalonate semialdehyde dehydrogenase deficiency in 2000 (Chambliss et al., PMID: 10947204). At least six unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 10947204, 21863277, 23835272, 32151545). No supporting segregation information is available. The disease mechanism appears to be biallelic loss-of-function, with a deficiency in the MMSDH protein leading to an increase in valine metabolites such as 3-hydroxyisobutyric acid and potentially the phenotypes seen in conjunction with the biochemical abnormality. This gene-disease relationship is supported by the biochemical function of methylmalonate semialdehyde dehydrogenase, which is consistent with the finding of persistently elevated 3-hydroxypropionate, 3-hydroxyisobutyrate, and β-aminoisobutyrate levels in patients with this condition (PMIDs: 3939535, 10971205, 32151545) In summary, there is limited evidence to support this gene-disease relationship. There is the question of whether the additional symptoms of some individuals are related to this disorder, although that is unrelated to the biochemical abnormality and the response to modified diet seems to indicate a connection. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/27/2019 (SOP Version 7). It was reevaluated on 10/14/2022 with no new evidence found. As a result of this reevaluation, the classification remained Limited.