ClinVar Genomic variation as it relates to human health
NM_001080.3(ALDH5A1):c.1226G>A (p.Gly409Asp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001080.3(ALDH5A1):c.1226G>A (p.Gly409Asp)
Variation ID: 1359 Accession: VCV000001359.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p22.3 6: 24528049 (GRCh38) [ NCBI UCSC ] 6: 24528277 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 2, 2015 May 12, 2024 May 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001080.3:c.1226G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001071.1:p.Gly409Asp missense NM_001368954.1:c.1082G>A NP_001355883.1:p.Gly361Asp missense NM_170740.1:c.1265G>A NP_733936.1:p.Gly422Asp missense NC_000006.12:g.24528049G>A NC_000006.11:g.24528277G>A NG_008161.1:g.38081G>A P51649:p.Gly409Asp - Protein change
- G409D, G422D, G361D
- Other names
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- Canonical SPDI
- NC_000006.12:24528048:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein interaction site Variation Ontology [VariO:0118]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ALDH5A1 | - | - |
GRCh38 GRCh37 |
613 | 827 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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May 23, 2023 | RCV000001424.26 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2022 | RCV001725927.17 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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Succinic semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236519.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893708.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Mar 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001554624.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 08, 2021)
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criteria provided, single submitter
Method: curation
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV002820022.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023
Comment:
enzyme activity <1%;catalytic domain
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Pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013924.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PM2, PP3, PP5
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000945689.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103, 28664505). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103, 28664505). 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. ClinVar contains an entry for this variant (Variation ID: 1359). This missense change has been observed in individual(s) with ALDH5A1-related disease (PMID: 14635103, 28664505). This variant is present in population databases (rs118203984, gnomAD 0.006%). 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). (less)
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Pathogenic
(Aug 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961935.15
First in ClinVar: Oct 08, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370109.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM2,PP3,PP4.
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573356.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Seizure (present) , Autism (present) , Thoracolumbar scoliosis (present) , Thoracic kyphosis (present) , Abnormal facial shape (present) , Exotropia (present) , Myopia (present) , … (more)
Seizure (present) , Autism (present) , Thoracolumbar scoliosis (present) , Thoracic kyphosis (present) , Abnormal facial shape (present) , Exotropia (present) , Myopia (present) , Amblyopia (present) , Pes planus (present) (less)
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Pathogenic
(Dec 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002499791.2
First in ClinVar: Apr 23, 2022 Last updated: Dec 17, 2022 |
Comment:
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); … (more)
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) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Succinate-semialdehyde dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003842258.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
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 … (more)
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. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Dec 01, 2003)
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no assertion criteria provided
Method: literature only
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SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021574.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 25, 2021 |
Comment on evidence:
In 6 unrelated families, Akaboshi et al. (2003) found that succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) was associated with a 1226G-A transition in the ALDH5A1 … (more)
In 6 unrelated families, Akaboshi et al. (2003) found that succinic semialdehyde dehydrogenase deficiency (SSADHD; 271980) was associated with a 1226G-A transition in the ALDH5A1 gene, resulting in a gly409-to-asp (G409D) substitution. The mutation occurred in homozygous or compound heterozygous state. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on protein interaction site
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV002820022.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1. | Brennenstuhl H | International journal of molecular sciences | 2020 | PMID: 33203024 |
SSADH deficiency in an Italian family: a novel ALDH5A1 gene mutation affecting the succinic semialdehyde substrate binding site. | Leo S | Metabolic brain disease | 2017 | PMID: 28664505 |
Mutation analysis and prenatal diagnosis in a Chinese family with succinic semialdehyde dehydrogenase and a systematic review of the literature of reported ALDH5A1 mutations. | Liu N | Journal of perinatal medicine | 2016 | PMID: 25431891 |
Neuropathology in succinic semialdehyde dehydrogenase deficiency. | Knerr I | Pediatric neurology | 2010 | PMID: 20304328 |
Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. | Akaboshi S | Human mutation | 2003 | PMID: 14635103 |
Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. | Hogema BM | Nature genetics | 2001 | PMID: 11544478 |
Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: increased accuracy employing DNA, enzyme, and metabolite analyses. | Hogema BM | Molecular genetics and metabolism | 2001 | PMID: 11243727 |
Text-mined citations for rs118203984 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.