NM_001080.3(ALDH5A1):c.123_127dup (p.Gln43fs) AND Succinate-semialdehyde dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 8, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001238508.8

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.123_127dup (p.Gln43fs)]

NM_001080.3(ALDH5A1):c.123_127dup (p.Gln43fs)

Genes:

LOC129995978:ATAC-STARR-seq lymphoblastoid silent region 16989 [Gene]
ALDH5A1:aldehyde dehydrogenase 5 family member A1 [Gene - OMIM - HGNC]
GPLD1:glycosylphosphatidylinositol specific phospholipase D1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

6p22.3

Genomic location:

Preferred name:

NM_001080.3(ALDH5A1):c.123_127dup (p.Gln43fs)

HGVS:

NC_000006.12:g.24495114GGCCC[3]
NG_008161.1:g.5146GGCCC[3]
NM_001080.3:c.123_127dupMANE SELECT
NM_001368954.1:c.123_127dup
NM_170740.1:c.123_127dup
NP_001071.1:p.Gln43fs
NP_001355883.1:p.Gln43fs
NP_733936.1:p.Gln43fs
NC_000006.11:g.24495337_24495338insGCCCG
NC_000006.11:g.24495342GGCCC[3]

Protein change:

Q43fs

Links:

dbSNP: rs1273153948

NCBI 1000 Genomes Browser:

rs1273153948

Molecular consequence:

NM_001080.3:c.123_127dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368954.1:c.123_127dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_170740.1:c.123_127dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Succinate-semialdehyde dehydrogenase deficiency (SSADHD)
Synonyms:: 4-hydroxybutyric aciduria; Gamma-hydroxybutyricaciduria
Identifiers:: MONDO: MONDO:0010083; MedGen: C0268631; Orphanet: 22; OMIM: 271980

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001411324	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14635103, 26220405, 28492532
SCV002819998	Elsea Laboratory, Baylor College of Medicine	criteria provided, single submitter (Martin et al. (J Child Neurol. 2021))	Pathogenic (Mar 8, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26220405, 34882073

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001411324

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002819998

Elsea Laboratory, Baylor College of Medicine

criteria provided, single submitter

(Martin et al. (J Child Neurol. 2021))

Pathogenic
(Mar 8, 2021)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Chinese	germline	yes	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

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, Hogema BM, Novelletto A, Malaspina P, Salomons GS, Maropoulos GD, Jakobs C, Grompe M, Gibson KM.

Hum Mutat. 2003 Dec;22(6):442-50.

PubMed [citation]

PMID:: 14635103

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001411324.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103). This variant has been observed in an individual affected with succinic semialdehyde dehydrogenase deficiency (PMID: 26220405). It is also known as c.127-128insGGCCC in the literature. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Gln43Argfs*50) in the ALDH5A1 gene. It is expected to result in an absent or disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Elsea Laboratory, Baylor College of Medicine, SCV002819998.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Chinese	not provided	not provided	not provided	curation	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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