ClinVar Genomic variation as it relates to human health

The ALDH5A1 c.589G>A (p.Val197Met) variant is a missense variant that has been reported in a compound heterozgyous state with a second missense variant in a child with succinic semialdehyde dehydrogenase (SSADH) deficiency (Liu et al. 2014). Family studies revealed that the child inherited the p.Val197Met variant from his mother and the second missense variant from his father. The p.Val197Met variant was absent from 100 healthy ethnically matched control individuals and is reported at a frequency of 0.000196 in the African population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Val197Met variant is thus classified as a variant of unknown significance but suspicious for pathogenicity 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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the ALDH5A1 protein (p.Val197Met). This variant is present in population databases (rs768219929, gnomAD 0.01%). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase (PMID: 25431891). ClinVar contains an entry for this variant (Variation ID: 356132). 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. 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.

Variant summary: ALDH5A1 c.589G>A (p.Val197Met) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250134 control chromosomes. c.589G>A has been reported in the literature in trans along with an apparently VUS missense in an individual affected with Succinic Semialdehyde Dehydrogenase Deficiency (Liu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Succinic Semialdehyde Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25431891).ClinVar contains an entry for this variant (Variation ID: 356132). Based on the evidence outlined above, the variant was classified as uncertain significance.

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: 26268900, 27268762, 12743223, 32402538, 34426522, 33203024, 25431891)

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.

The ALDH5A1 p.Val197Met variant was identified in dbSNP (ID: rs768219929) as "With Uncertain significance allele" and in Clinvar (classified as VUS by Ambry Genetics, Illumina Clinical Services, and EGL Diagnostics with the associated conditions of Succinate-semialdehyde dehydrogenase deficiency and inborn genetic diseases). The variant was not identified in Cosmic and LOVD 3.0 databases. The variant was also found in control databases in 12 of 281530 chromosomes at a frequency of 0.000043 (Genome Aggregation Database Feb 27, 2017), in the following populations: Latino in 5 of 35406 chromosomes (freq: 0.000141), Other in 1 of 7202 chromosomes (freq: 0.000139), African in 2 of 24914 chromosomes (freq: 0.00008) and European (non-Finnish) in 4 of 128826 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. In a case study, genetic analysis of ALDH5A1 was performed for a male child with SSADH deficiency, his parents, and their 10 weeks' gestation at-risk fetus as well as 100 healthy unrelated volunteers. The proband was identified to have compound heterozygous mutations c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis (Liu_2016_PMID: 25431891). The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder) predict a greater than 10% difference in splicing (gain of a 5' splice site at c.586). The p.Val197 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.