ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 268 of the ALDH5A1 protein (p.Gly268Glu). This variant is present in population databases (rs375628463, gnomAD 0.01%). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 11243727, 14635103, 27104484). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 235512). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH5A1 protein function. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103). For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate that G268E results in loss of SSADH enzymatic activity (PMID: 14635103, 32402538); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27104484, 25525159, 20174634, 19300440, 37962671, 31515079, 31440721, 32402538, 23825041, 26964512, 20804942, 11243727, 14635103, 25558043, 33203024)

Variant summary: ALDH5A1 c.803G>A (p.Gly268Glu) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251478 control chromosomes (gnomAD). c.803G>A has been reported in the literature in individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (example: Akaboshi_2003). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Akaboshi_ALDH5A1_HumMutat_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11243727, 14635103). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Gly268Glu variant in the ALDH5A1 gene has been previously reported in 7 unrelated individuals with succinic semialdehyde dehydrogenase deficiency (Akaboshi, et al., 2003, Hogema et al., 2001; Horvath et al., 2016). All affected individuals were compound heterozygotes. This variant was determined to be in trans with a disease-associated variant (p.Trp204*, p.Arg412*), consistent with autosomal recessive inheritance. The presence of this variant with a likely disease causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has also been identified in 24/282406 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies of the p.Gly268Glu variant suggest a deleterious effect to the protein that is sufficient to be disease-causing (Akaboshi et al., 2003; Hogema et al., 2001). Computational tools predict that the p.Gly268Glu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Gly268Glu variant as pathogenic for autosomal recessive succinic semialdehyde dehydrogenase deficiency based on the information above. [ACMG evidence codes used: PS4; PS3_Moderate; PM2; PM3; PP3]

The ALDH5A1 c.803G>A variant is predicted to result in the amino acid substitution p.Gly268Glu. This variant has been reported in the compound heterozygous state in several individuals with succinic semialdehyde dehydrogenase deficiency (SSADH) (Hogema et al. 2001. PubMed ID: 11243727; Horvath et al. 2016. PubMed ID: 27104484; Latzer et al. 2023. PubMed ID: 37962671). Functional studies using HEK293 cells indicated that the p.Gly268Glu decreased succinate semialdehyde dehydrogenase activity to less than 1% (Akaboshi et al. 2003. PubMed ID: 14635103). In silico structural modeling predicts the Gly268 residue maintains stability of the alpha-helix, which is a crucial component of NAD+ binding. This variant loosens critical interactions necessary for proper binding, negatively affecting protein function and stability (Latzer et al. 2023. PubMed ID: 37962671). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.