NM_001080.3(ALDH5A1):c.1478A>G (p.Asn493Ser) AND Succinate-semialdehyde dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 8, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000634939.6

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.1478A>G (p.Asn493Ser)]

NM_001080.3(ALDH5A1):c.1478A>G (p.Asn493Ser)

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.1478A>G (p.Asn493Ser)

HGVS:

NC_000006.12:g.24533582A>G
NG_008161.1:g.43614A>G
NM_001080.3:c.1478A>GMANE SELECT
NM_001368954.1:c.1334A>G
NM_170740.1:c.1517A>G
NP_001071.1:p.Asn493Ser
NP_001355883.1:p.Asn445Ser
NP_733936.1:p.Asn506Ser
NC_000006.11:g.24533810A>G

Protein change:

N445S

Links:

dbSNP: rs776978579

NCBI 1000 Genomes Browser:

rs776978579

Molecular consequence:

NM_001080.3:c.1478A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001368954.1:c.1334A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170740.1:c.1517A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on protein interaction site [Variation Ontology: 0118]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000756311	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002820040	Elsea Laboratory, Baylor College of Medicine	criteria provided, single submitter (Martin et al. (J Child Neurol. 2021))	Likely pathogenic (Mar 8, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 32402538, 33203024, 34882073

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000756311

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 12, 2017)

germline

clinical testing

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

SCV002820040

Elsea Laboratory, Baylor College of Medicine

criteria provided, single submitter

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

Likely pathogenic
(Mar 8, 2021)

germline

curation

PubMed (3)
[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	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

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

Functional analysis of thirty-four suspected pathogenic missense variants in ALDH5A1 gene associated with succinic semialdehyde dehydrogenase deficiency.

Pop A, Smith DEC, Kirby T, Walters D, Gibson KM, Mahmoudi S, van Dooren SJM, Kanhai WA, Fernandez-Ojeda MR, Wever EJM, Koster J, Waterham HR, Grob B, Roos B, Wamelink MMC, Chen J, Natesan S, Salomons GS.

Mol Genet Metab. 2020 Jul;130(3):172-178. doi: 10.1016/j.ymgme.2020.04.004. Epub 2020 May 4.

PubMed [citation]

PMID:: 32402538

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000756311.1

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

Description

This sequence change replaces asparagine with serine at codon 493 of the ALDH5A1 protein (p.Asn493Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs776978579, ExAC 0.001%). This variant has not been reported in the literature in individuals with ALDH5A1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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, SCV002820040.1

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

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine