chr6-24503413-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong

The NM_001080.3(ALDH5A1):c.589G>A(p.Val197Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,613,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:1

Conservation

PhyloP100: 9.59

Variant links:

Genes affected

ALDH5A1 (HGNC:408): (aldehyde dehydrogenase 5 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ALDH5A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001080.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.73405 (below the threshold of 3.09). Trascript score misZ: 0.28023 (below the threshold of 3.09). GenCC associations: The gene is linked to succinic semialdehyde dehydrogenase deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3 link	c.589G>A	p.Val197Met	missense_variant	Exon 3 of 10	ENST00000357578.8	NP_001071.1	P51649-1X5DQN2
ALDH5A1	NM_170740.1 link	c.589G>A	p.Val197Met	missense_variant	Exon 3 of 11		NP_733936.1	P51649-2X5D299
ALDH5A1	NM_001368954.1 link	c.589G>A	p.Val197Met	missense_variant	Exon 3 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.589G>A	p.Val197Met	missense_variant	Exon 3 of 10	1	NM_001080.3	ENSP00000350191.3		P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000440

AC:

AN:

250134

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1460796

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.000224

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26128

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000464

AC:

AN:

86252

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52472

Gnomad4 NFE exome

AF:

0.0000612

AC:

AN:

1111918

Gnomad4 Remaining exome

AF:

0.000182

AC:

AN:

60374

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000724

AC:

0.0000723519

AN:

0.0000723519

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000293962

AN:

0.0000293962

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000906

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Pathogenic:1Uncertain:2Benign:1

Jun 05, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2021

Elsea Laboratory, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 20, 2024

3billion

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Uncertain:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Mar 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALDH5A1 c.589G>A (p.Val197Met) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250134 control chromosomes. c.589G>A has been reported in the literature in trans along with an apparently VUS missense in an individual affected with Succinic Semialdehyde Dehydrogenase Deficiency (Liu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Succinic Semialdehyde Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25431891).ClinVar contains an entry for this variant (Variation ID: 356132). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jul 25, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;.;H

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MVP

0.99

MPC

0.94

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.96

Mutation Taster

=2/98

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over