ClinVar Genomic variation as it relates to human health
NM_001080.3(ALDH5A1):c.608C>T (p.Pro203Leu)
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
-
NM_001080.3(ALDH5A1):c.608C>T (p.Pro203Leu)
Variation ID: 1334843 Accession: VCV001334843.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p22.3 6: 24503432 (GRCh38) [ NCBI UCSC ] 6: 24503660 (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 Jan 26, 2022 Feb 14, 2024 Jun 2, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001080.3:c.608C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001071.1:p.Pro203Leu missense NM_001368954.1:c.608C>T NP_001355883.1:p.Pro203Leu missense NM_170740.1:c.608C>T NP_733936.1:p.Pro203Leu missense NC_000006.12:g.24503432C>T NC_000006.11:g.24503660C>T NG_008161.1:g.13464C>T - Protein change
- P203L
- Other names
- -
- Canonical SPDI
- NC_000006.12:24503431:C: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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 |
610 | 824 |
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. |
---|---|---|---|---|
no classifications from unflagged records (1) |
no classifications from unflagged records
|
Oct 2, 2023 | RCV001815110.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 8, 2022 | RCV001885302.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 2, 2023 | RCV002307765.3 |
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
(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: SCV002819983.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023
Comment:
NAD binding domain;deficient enzyme activity
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820259.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.P203L in ALDH5A1 (NM_001080.3) has been previously reported in affected patients, most recently in twins of Indian origin (Pop A et al, … (more)
The missense variant p.P203L in ALDH5A1 (NM_001080.3) has been previously reported in affected patients, most recently in twins of Indian origin (Pop A et al, Pearl P et al, Attri SV et al). The p.P203L variant is observed in 2/30,592 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P203L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 203 of ALDH5A1 is conserved in all mammalian species. The nucleotide c.608 in ALDH5A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Encephalopathy (present) , Seizure (present)
|
|
Pathogenic
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002601216.3
First in ClinVar: Nov 19, 2022 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate that this variant damages normal protein function (Pop et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate that this variant damages normal protein function (Pop et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25558043, 33203024, 32402538, 26268900, 34882073, 31069529, 27815844) (less)
|
|
Pathogenic
(Nov 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Succinate-semialdehyde dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002229776.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro203 amino acid residue in ALDH5A1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro203 amino acid residue in ALDH5A1. Other variant(s) that disrupt this residue have been observed in individuals with ALDH5A1-related conditions (PMID: 26268900), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 32402538). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1334843). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 27815844). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the ALDH5A1 protein (p.Pro203Leu). (less)
|
|
Uncertain significance
(Feb 21, 2018)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002061994.1
First in ClinVar: Jan 26, 2022 Last updated: Jan 26, 2022 |
|
|
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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: SCV002819983.1
|
|
Citations for germline classification of this variant
HelpTitle | 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 |
Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency. | Attri SV | JIMD reports | 2017 | PMID: 27815844 |
Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. | Lapalme-Remis S | Neurology | 2015 | PMID: 26268900 |
Text-mined citations for rs906284769 ...
HelpRecord last updated May 08, 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.