NM_001080.3(ALDH5A1):c.566_567insTTGCCCT (p.Val190fs) AND Succinate-semialdehyde dehydrogenase deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000820918.5

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.566_567insTTGCCCT (p.Val190fs)]

NM_001080.3(ALDH5A1):c.566_567insTTGCCCT (p.Val190fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

6p22.3

Genomic location:

Preferred name:

NM_001080.3(ALDH5A1):c.566_567insTTGCCCT (p.Val190fs)

HGVS:

NC_000006.12:g.24503390_24503391insTTGCCCT
NG_008161.1:g.13422_13423insTTGCCCT
NM_001080.3:c.566_567insTTGCCCTMANE SELECT
NM_001368954.1:c.566_567insTTGCCCT
NM_170740.1:c.566_567insTTGCCCT
NP_001071.1:p.Val190fs
NP_001355883.1:p.Val190fs
NP_733936.1:p.Val190fs
NC_000006.11:g.24503613_24503614insGCCCTTT
NC_000006.11:g.24503618_24503619insTTGCCCT

Protein change:

V190fs

Links:

dbSNP: rs755029414

NCBI 1000 Genomes Browser:

rs755029414

Molecular consequence:

NM_001080.3:c.566_567insTTGCCCT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368954.1:c.566_567insTTGCCCT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_170740.1:c.566_567insTTGCCCT - 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
SCV000961656	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14635103, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000961656

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2023)

germline

clinical testing

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000961656.4

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

Description

This sequence change creates a premature translational stop signal (p.Val190Cysfs*55) 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). This variant is present in population databases (rs755029414, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ALDH5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 663114). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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