The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). 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: 0.64). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000449408). The variant 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, 17438226, 27104484). A different missense change at the same codon (p.Cys93Arg) has been reported to be associated with ALDH5A1 related disorder (PMID: 32402538). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_001080.3(ALDH5A1):c.278G>T (p.Cys93Phe)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001080.3(ALDH5A1):c.278G>T (p.Cys93Phe)
Variation ID: 449408 Accession: VCV000449408.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p22.3 6: 24495274 (GRCh38) [ NCBI UCSC ] 6: 24495502 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 Feb 14, 2024 Nov 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001080.3:c.278G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001071.1:p.Cys93Phe missense NM_001368954.1:c.278G>T NP_001355883.1:p.Cys93Phe missense NM_170740.1:c.278G>T NP_733936.1:p.Cys93Phe missense NC_000006.12:g.24495274G>T NC_000006.11:g.24495502G>T NG_008161.1:g.5306G>T - Protein change
- C93F
- Other names
- -
- Canonical SPDI
- NC_000006.12:24495273:G:T
-
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]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00019
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| ALDH5A1 | - | - |
GRCh38 GRCh37 |
617 | 835 | |
| GPLD1 | - | - |
GRCh38 GRCh37 |
58 | 229 | |
| LOC129995978 | - | - | - | GRCh38 | - | 202 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 25, 2023 | RCV000521746.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2023 | RCV000700364.14 |
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
Help
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
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 the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893706.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Mar 08, 2021)
|
criteria provided, single submitter
Method: curation
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Elsea Laboratory, Baylor College of Medicine
Accession: SCV002819953.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023
Comment:
enzyme activity ~3%; NAD binding domain
|
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841899.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). 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: 0.004%). 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: 0.64). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000449408). The variant 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, 17438226, 27104484). A different missense change at the same codon (p.Cys93Arg) has been reported to be associated with ALDH5A1 related disorder (PMID: 32402538). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Moderate global developmental delay (present) , Macrocephaly (present) , Broad forehead (present) , Short nose (present) , Narrow naris (present) , Low-set ears (present) , … (more)
Moderate global developmental delay (present) , Macrocephaly (present) , Broad forehead (present) , Short nose (present) , Narrow naris (present) , Low-set ears (present) , Preauricular skin tag (present) , Mandibular prognathia (present) (less)
|
|
|
Pathogenic
(Aug 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617541.2
First in ClinVar: Dec 19, 2017 Last updated: Aug 31, 2023 |
Comment:
Published functional studies of the C93F variant indicate an almost complete loss of enzyme activity, below 5% normal levels (Akaboshi et al., 2003); In silico … (more)
Published functional studies of the C93F variant indicate an almost complete loss of enzyme activity, below 5% normal levels (Akaboshi et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27104484, 12555945, 32395407, 31589614, 31440721, 25558043, 14635103, 20973619, 20018576, 16442322, 17438226, 23430864, 30109838, 31267348, 33203024) (less)
|
|
|
Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000829116.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 93 of the ALDH5A1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 93 of the ALDH5A1 protein (p.Cys93Phe). This variant is present in population databases (rs765561257, gnomAD 0.01%). This missense change has been observed in individual(s) with succinate semialdehyde dehydrogenase deficiency (PMID: 14635103, 23430864). 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: 449408). 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. (less)
|
Comment:
Comment:
Published functional studies of the C93F variant indicate an almost complete loss of enzyme activity, below 5% normal levels (Akaboshi et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27104484, 12555945, 32395407, 31589614, 31440721, 25558043, 14635103, 20973619, 20018576, 16442322, 17438226, 23430864, 30109838, 31267348, 33203024)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 93 of the ALDH5A1 protein (p.Cys93Phe). This variant is present in population databases (rs765561257, gnomAD 0.01%). This missense change has been observed in individual(s) with succinate semialdehyde dehydrogenase deficiency (PMID: 14635103, 23430864). 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: 449408). 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.
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
Help
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. |
|---|---|---|---|---|
|
effect on protein interaction site
|
Elsea Laboratory, Baylor College of Medicine
Accession: SCV002819953.1
|
|
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). 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: 0.64). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000449408). The variant 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, 17438226, 27104484). A different missense change at the same codon (p.Cys93Arg) has been reported to be associated with ALDH5A1 related disorder (PMID: 32402538). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Published functional studies of the C93F variant indicate an almost complete loss of enzyme activity, below 5% normal levels (Akaboshi et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27104484, 12555945, 32395407, 31589614, 31440721, 25558043, 14635103, 20973619, 20018576, 16442322, 17438226, 23430864, 30109838, 31267348, 33203024)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 93 of the ALDH5A1 protein (p.Cys93Phe). This variant is present in population databases (rs765561257, gnomAD 0.01%). This missense change has been observed in individual(s) with succinate semialdehyde dehydrogenase deficiency (PMID: 14635103, 23430864). 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: 449408). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Functional analysis of thirty-four suspected pathogenic missense variants in ALDH5A1 gene associated with succinic semialdehyde dehydrogenase deficiency. | Pop A | Molecular genetics and metabolism | 2020 | PMID: 32402538 |
| Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency. | Horvath GA | Neuropediatrics | 2016 | PMID: 27104484 |
| Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency. | Casarano M | JIMD reports | 2012 | PMID: 23430864 |
| Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency. | Leuzzi V | Neurology | 2007 | PMID: 17438226 |
| 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 |
Text-mined citations for rs765561257 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.