NM_001080.3(ALDH5A1):c.589G>A (p.Val197Met) AND Succinate-semialdehyde dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Sep 20, 2024
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:: RCV000371631.16

Allele description [Variation Report for NM_001080.3(ALDH5A1):c.589G>A (p.Val197Met)]

NM_001080.3(ALDH5A1):c.589G>A (p.Val197Met)

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.589G>A (p.Val197Met)

HGVS:

NC_000006.12:g.24503413G>A
NG_008161.1:g.13445G>A
NM_001080.3:c.589G>AMANE SELECT
NM_001368954.1:c.589G>A
NM_170740.1:c.589G>A
NP_001071.1:p.Val197Met
NP_001355883.1:p.Val197Met
NP_733936.1:p.Val197Met
NC_000006.11:g.24503641G>A

Protein change:

V197M

Links:

dbSNP: rs768219929

NCBI 1000 Genomes Browser:

rs768219929

Molecular consequence:

NM_001080.3:c.589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368954.1:c.589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170740.1:c.589G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000461817	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Jul 10, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000941099	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25431891, 28492532
SCV001760956	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jun 5, 2020)	germline	clinical testing	Citation Link,
SCV002819981	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] 25431891, 33203024, 34882073
SCV005328731	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 20, 2024)	germline	clinical testing	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	unknown	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	no	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

Mutation analysis and prenatal diagnosis in a Chinese family with succinic semialdehyde dehydrogenase and a systematic review of the literature of reported ALDH5A1 mutations.

Liu N, Kong XD, Kan QC, Shi HR, Wu QH, Zhuo ZH, Bai QL, Jiang M.

J Perinat Med. 2016 May 1;44(4):441-51. doi: 10.1515/jpm-2014-0164. Review.

PubMed [citation]

PMID:: 25431891

See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000461817.3

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

Description

The ALDH5A1 c.589G>A (p.Val197Met) variant is a missense variant that has been reported in a compound heterozgyous state with a second missense variant in a child with succinic semialdehyde dehydrogenase (SSADH) deficiency (Liu et al. 2014). Family studies revealed that the child inherited the p.Val197Met variant from his mother and the second missense variant from his father. The p.Val197Met variant was absent from 100 healthy ethnically matched control individuals and is reported at a frequency of 0.000196 in the African population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Val197Met variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for succinic semialdehyde dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000941099.5

#	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 replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the ALDH5A1 protein (p.Val197Met). This variant is present in population databases (rs768219929, gnomAD 0.01%). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase (PMID: 25431891). ClinVar contains an entry for this variant (Variation ID: 356132). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH5A1 protein function. 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 New York Genome Center - CSER-NYCKidSeq, SCV001760956.1

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

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

From Elsea Laboratory, Baylor College of Medicine, SCV002819981.1

#	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

From 3billion, SCV005328731.1

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

Description

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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