NM_001080.3:c.1226G>A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001080.3(ALDH5A1):c.1226G>A(p.Gly409Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001080.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.1226G>A | p.Gly409Asp | missense_variant | Exon 8 of 10 | ENST00000357578.8 | NP_001071.1 | |
ALDH5A1 | NM_170740.1 | c.1265G>A | p.Gly422Asp | missense_variant | Exon 9 of 11 | NP_733936.1 | ||
ALDH5A1 | NM_001368954.1 | c.1082G>A | p.Gly361Asp | missense_variant | Exon 7 of 9 | NP_001355883.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251424Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135878
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727230
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Pathogenic:10
- -
- -
- -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14635103). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.87). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001359). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14635103 , 28664505). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 409 of the ALDH5A1 protein (p.Gly409Asp). This variant is present in population databases (rs118203984, gnomAD 0.006%). This missense change has been observed in individual(s) with ALDH5A1-related disease (PMID: 14635103, 28664505). ClinVar contains an entry for this variant (Variation ID: 1359). 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, 28664505). For these reasons, this variant has been classified as Pathogenic. -
- -
A Heterozygous Missense variant c.1226G>A in Exon 8 of the ALDH5A1 gene that results in the amino acid substitution p.Gly409Asp was identified. The observed variant has a minor allele frequency of 0.00003 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 1359]. The observed variation has previously been reported for Succinic Semialdehyde Dehydrogenase Deficiency by Brennenstuhl, Heiko, et al., 2020. For these reasons this variant has been classified as Likely Pathogenic. -
Variant summary: ALDH5A1 c.1226G>A (p.Gly409Asp) 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 2.8e-05 in 251424 control chromosomes. c.1226G>A has been reported in the literature as homozygous or compound heterozygous with another pathogenic variant in multiple individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (e.g. Hogema_2001, Akaboshi_2003, Knerr_2010, Leo_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal SSADH activity (e.g. Hogema_2001, Akaboshi_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
PS3, PM2, PP3, PP5 -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM2,PP3,PP4. -
not provided Pathogenic:2
Published functional studies demonstrate that this variant was reported to have SSADH enzyme activity of less than 1% relative to wild-type (Akaboshi et al., 2003); 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: 30829465, 11243727, 20304328, 28664505, 14635103, 32395407, 33531951, 32093054, 32402538, 33203024, 32887777) -
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at