ALDH5A1

protein-coding

aldehyde dehydrogenase 5 family member A1, the group of Aldehyde dehydrogenases

Gene summary

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]

MANE transcript

NM_001080.3

Inheritance

ClinVar variants

P:159U:279B:201

Top phenotype

Succinic semialdehyde dehydrogenase deficiency

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr6:24,494,867-24,537,207

External References & Databases

Ensembl (ENSG00000112294)

Transcript & Mutation Effects

hg38 • Region Span ~42.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

succinic semialdehyde dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010083

Submitter: Labcorp Genetics (formerly Invitae)

succinic semialdehyde dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010083

Submitter: ClinGen

*ALDH5A1* was first reported in relation to autosomal recessive succinic semialdehyde dehydrogenase deficiency (SSADHD) in 1998 (Chambliss et al., PMID: 9683595). *ALDH5A1* encodes the succinic semialdehyde dehydrogenase enzyme, which is involved in the degradation pathway of GABA. SSADHD is a rare neurometabolic disorder characterized by developmental delay, hypotonia, intellectual disability, ataxia, seizures, and behavioral problems. Approximately 50 pathogenic variants have been reported in the literature, including large deletions, and frameshift, nonsense and missense variants predicted or shown to cause loss or reduced enzyme function. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence, including a mouse model and *in vitro* assays of SSADH activity. In summary, there is definitive evidence supporting the relationship between *ALDH5A1* and autosomal recessive succinic semialdehyde dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 27, 2021 (SOP Version 8).

succinic semialdehyde dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010083

Submitter: Orphanet

succinic semialdehyde dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010083

Submitter: PanelApp Australia

succinic semialdehyde dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010083

Submitter: G2P

Clinical Genomic Database (CGD)

Succinic semialdehyde dehydrogenase deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7226548; 6627675; 9266358; 9093300; 9683595; 12743223; 14635103; 15059623; 17438226; 20304328; 21612881; 22437753; 32887777

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALDH5A1 variants in ClinVar

13 Conditions Cataloged

Succinate-semialdehyde dehydrogenase deficiencyTotal: 698

not providedTotal: 177

Inborn genetic diseasesTotal: 53

not specifiedTotal: 49

ALDH5A1-related disorderTotal: 28

Intellectual disabilityTotal: 4

See casesTotal: 2

Likely inborn error of metabolismTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		4 clinvar	177 clinvar	3 clinvar	185
missense	15 clinvar	53 clinvar	271 clinvar	19 clinvar	2 clinvar	360
nonsense	17 clinvar	6 clinvar				23
start loss			1 clinvar			1
frameshift	35 clinvar	14 clinvar				49
splice donor/acceptor (+/-2bp)	11 clinvar	7 clinvar	3 clinvar			21
Total	79	80	279	196	5	639

Highest pathogenic variant AF is 0.00024846368

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080.3	RefSeq	NP_001071.1	10	MANE Select
ENST00000357578.8	Ensembl	ENSP00000350191.3	10	MANE Select
NM_001368954.1	RefSeq	NP_001355883.1	9	Standard
NM_170740.1	RefSeq	NP_733936.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Butanoate metabolism - Homo sapiens (human)
Valproic Acid Pathway, Pharmacodynamics
Pathway_PA165964473
Cyclophosphamide Pathway, Pharmacodynamics

Biological Process

glucose metabolic process
acetate metabolic process
succinate metabolic process
glutamate metabolic process
glutamine metabolic process

Molecular Function

succinate-semialdehyde dehydrogenase (NAD+) activity
succinate-semialdehyde dehydrogenase [NAD(P)+] activity
protein homodimerization activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000348925
Coding exons: 11
Length: 42356
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 81
Defined: 125748
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.734	254	289	0.879	0.0000162	3483
Missense (PolyPhen)		102	125.43	0.81322		1393
Synonymous	0.539	112	119	0.937	0.00000763	1152
Loss of Function	1.79	14	23.4	0.599	0.00000116	280

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00043	0.00043	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). {ECO:0000269|PubMed:19300440}.;

Recessive Scores

pRec: 0.212

Intolerance Scores

LoFtool: 0.331
RVIS EVS: 0.4
RVIS percentile EVS: 76.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.974

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium