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NM_001080.3(ALDH5A1):c.803G>A (p.Gly268Glu) AND ALDH5A1-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 26, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004745292.1

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.803G>A (p.Gly268Glu)]

NM_001080.3(ALDH5A1):c.803G>A (p.Gly268Glu)

Gene:
ALDH5A1:aldehyde dehydrogenase 5 family member A1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p22.3
Genomic location:
Preferred name:
NM_001080.3(ALDH5A1):c.803G>A (p.Gly268Glu)
Other names:
p.Gly268Glu
HGVS:
  • NC_000006.12:g.24515243G>A
  • NG_008161.1:g.25275G>A
  • NM_001080.3:c.803G>AMANE SELECT
  • NM_001368954.1:c.727-5158G>A
  • NM_170740.1:c.842G>A
  • NP_001071.1:p.Gly268Glu
  • NP_733936.1:p.Gly281Glu
  • NC_000006.11:g.24515471G>A
Protein change:
G268E
Links:
dbSNP: rs375628463
NCBI 1000 Genomes Browser:
rs375628463
Molecular consequence:
  • NM_001368954.1:c.727-5158G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001080.3:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170740.1:c.842G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
effect on protein interaction site [Variation Ontology: 0118]

Condition(s)

Name:
ALDH5A1-related disorder
Synonyms:
ALDH5A1-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005360703PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jul 26, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005360703.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ALDH5A1 c.803G>A variant is predicted to result in the amino acid substitution p.Gly268Glu. This variant has been reported in the compound heterozygous state in several individuals with succinic semialdehyde dehydrogenase deficiency (SSADH) (Hogema et al. 2001. PubMed ID: 11243727; Horvath et al. 2016. PubMed ID: 27104484; Latzer et al. 2023. PubMed ID: 37962671). Functional studies using HEK293 cells indicated that the p.Gly268Glu decreased succinate semialdehyde dehydrogenase activity to less than 1% (Akaboshi et al. 2003. PubMed ID: 14635103). In silico structural modeling predicts the Gly268 residue maintains stability of the alpha-helix, which is a crucial component of NAD+ binding. This variant loosens critical interactions necessary for proper binding, negatively affecting protein function and stability (Latzer et al. 2023. PubMed ID: 37962671). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024