NM_001080.3(ALDH5A1):c.967_968dup (p.Gln323fs) AND Succinate-semialdehyde dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 25, 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:: RCV001386894.7

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.967_968dup (p.Gln323fs)]

NM_001080.3(ALDH5A1):c.967_968dup (p.Gln323fs)

Gene:

ALDH5A1:aldehyde dehydrogenase 5 family member A1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

6p22.3

Genomic location:

Preferred name:

NM_001080.3(ALDH5A1):c.967_968dup (p.Gln323fs)

HGVS:

NC_000006.12:g.24520497_24520498dup
NG_008161.1:g.30529_30530dup
NM_001080.3:c.967_968dupMANE SELECT
NM_001368954.1:c.823_824dup
NM_170740.1:c.1006_1007dup
NP_001071.1:p.Gln323fs
NP_001355883.1:p.Gln275fs
NP_733936.1:p.Gln336fs
NC_000006.11:g.24520724_24520725insCA
NC_000006.11:g.24520725_24520726dup

Protein change:

Q275fs

Links:

dbSNP: rs747336313

NCBI 1000 Genomes Browser:

rs747336313

Molecular consequence:

NM_001080.3:c.967_968dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368954.1:c.823_824dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_170740.1:c.1006_1007dup - 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
SCV001587292	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 25, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32887777, 14635103, 28492532
SCV002820015	Elsea Laboratory, Baylor College of Medicine	criteria provided, single submitter (Martin et al. (J Child Neurol. 2021))	Pathogenic (Mar 8, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001587292

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 25, 2021)

germline

clinical testing

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

SCV002820015

Elsea Laboratory, Baylor College of Medicine

criteria provided, single submitter

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

Pathogenic
(Mar 8, 2021)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Novel ALDH5A1 variants and genotype: Phenotype correlation in SSADH deficiency.

DiBacco ML, Pop A, Salomons GS, Hanson E, Roullet JB, Gibson KM, Pearl PL.

Neurology. 2020 Nov 10;95(19):e2675-e2682. doi: 10.1212/WNL.0000000000010730. Epub 2020 Sep 4.

PubMed [citation]

PMID:: 32887777
PMCID:: PMC7713737

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

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001587292.4

#	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. This variant has been observed in individual(s) with ALDH5A1-related conditions (PMID: 32887777). This variant is present in population databases (rs747336313, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Gln323Hisfs*4) in the ALDH5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103).

#	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, SCV002820015.1

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

#	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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