NM_001080.3(ALDH5A1):c.589G>A (p.Val197Met) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 11, 2024
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:: RCV000730082.7

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000857793	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Nov 14, 2017)	germline	clinical testing	Citation Link,
SCV001552383	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV005188819	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV005325144	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 11, 2024)	germline	clinical testing	Citation Link

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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	clinical testing, not provided
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Eurofins Ntd Llc (ga), SCV000857793.1

#	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	not provided	not provided	not provided		1	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552383.1

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

Description

The ALDH5A1 p.Val197Met variant was identified in dbSNP (ID: rs768219929) as "With Uncertain significance allele" and in Clinvar (classified as VUS by Ambry Genetics, Illumina Clinical Services, and EGL Diagnostics with the associated conditions of Succinate-semialdehyde dehydrogenase deficiency and inborn genetic diseases). The variant was not identified in Cosmic and LOVD 3.0 databases. The variant was also found in control databases in 12 of 281530 chromosomes at a frequency of 0.000043 (Genome Aggregation Database Feb 27, 2017), in the following populations: Latino in 5 of 35406 chromosomes (freq: 0.000141), Other in 1 of 7202 chromosomes (freq: 0.000139), African in 2 of 24914 chromosomes (freq: 0.00008) and European (non-Finnish) in 4 of 128826 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. In a case study, genetic analysis of ALDH5A1 was performed for a male child with SSADH deficiency, his parents, and their 10 weeks' gestation at-risk fetus as well as 100 healthy unrelated volunteers. The proband was identified to have compound heterozygous mutations c.496T>C (p.W166R) and c.589G>A (p.V197M). Each of his parents carried a mutation. DNA sequencing of chorionic villus revealed the fetus was a carrier and this was confirmed after birth by genetic analysis of umbilical cord blood and urine organic acid analysis (Liu_2016_PMID: 25431891). The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder) predict a greater than 10% difference in splicing (gain of a 5' splice site at c.586). The p.Val197 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From Breakthrough Genomics, Breakthrough Genomics, SCV005188819.1

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

From GeneDx, SCV005325144.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26268900, 27268762, 12743223, 32402538, 34426522, 33203024, 25431891)

#	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: Oct 8, 2024

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Relating variation to medicine