rs375628463
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001080.3(ALDH5A1):c.803G>A(p.Gly268Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,390 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
ALDH5A1
NM_001080.3 missense
NM_001080.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 8.81
Genes affected
ALDH5A1 (HGNC:408): (aldehyde dehydrogenase 5 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
Variant 6-24515243-G-A is Pathogenic according to our data. Variant chr6-24515243-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 235512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24515243-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH5A1 | NM_001080.3 | c.803G>A | p.Gly268Glu | missense_variant | 5/10 | ENST00000357578.8 | |
ALDH5A1 | NM_170740.1 | c.842G>A | p.Gly281Glu | missense_variant | 6/11 | ||
ALDH5A1 | NM_001368954.1 | c.727-5158G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH5A1 | ENST00000357578.8 | c.803G>A | p.Gly268Glu | missense_variant | 5/10 | 1 | NM_001080.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000858 AC: 13AN: 151558Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251478Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135912
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GnomAD4 exome AF: 0.000196 AC: 287AN: 1461832Hom.: 0 Cov.: 34 AF XY: 0.000187 AC XY: 136AN XY: 727214
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Succinate-semialdehyde dehydrogenase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | curation | Elsea Laboratory, Baylor College of Medicine | Mar 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 01, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 19, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Oct 28, 2020 | 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] - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2023 | Published functional studies demonstrate that G268E results in loss of SSADH enzymatic activity (Akaboshi et al., 2003; Pop et al., 2020); 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: 27104484, 25525159, 20174634, 19300440, 31515079, 31440721, 32402538, 23825041, 26964512, 20804942, 11243727, 14635103, 25558043, 33203024) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 09, 2015 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at