rs118203984

Positions:

chr6-24528049-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000357578.8(ALDH5A1):c.1226G>A(p.Gly409Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,614,036 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ALDH5A1
ENST00000357578.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.74

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 made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 6-24528049-G-A is Pathogenic according to our data. Variant chr6-24528049-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24528049-G-A is described in Lovd as [Pathogenic]. Variant chr6-24528049-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH5A1	NM_001080.3 linkuse as main transcript	c.1226G>A	p.Gly409Asp	missense_variant	8/10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1 linkuse as main transcript	c.1265G>A	p.Gly422Asp	missense_variant	9/11		NP_733936.1
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.1082G>A	p.Gly361Asp	missense_variant	7/9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.1226G>A	p.Gly409Asp	missense_variant	8/10	1	NM_001080.3	ENSP00000350191	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251424

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000346

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Pathogenic:10

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 23, 2023	PS3, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	curation	Elsea Laboratory, Baylor College of Medicine	Mar 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 05, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PM2,PP3,PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.1226G>A in Exon 8 of the ALDH5A1 gene that results in the amino acid substitution p.Gly409Asp was identified. The observed variant has a minor allele frequency of 0.00003 in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 1359]. The observed variation has previously been reported for Succinic Semialdehyde Dehydrogenase Deficiency by Brennenstuhl, Heiko, et al., 2020. For these reasons this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Aug 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2021	Variant summary: ALDH5A1 c.1226G>A (p.Gly409Asp) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251424 control chromosomes. c.1226G>A has been reported in the literature as homozygous or compound heterozygous with another pathogenic variant in multiple individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (e.g. Hogema_2001, Akaboshi_2003, Knerr_2010, Leo_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal SSADH activity (e.g. Hogema_2001, Akaboshi_2003). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14635103). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.87). The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001359). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14635103 , 28664505). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103, 28664505). 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. ClinVar contains an entry for this variant (Variation ID: 1359). This missense change has been observed in individual(s) with ALDH5A1-related disease (PMID: 14635103, 28664505). This variant is present in population databases (rs118203984, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 409 of the ALDH5A1 protein (p.Gly409Asp). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2022	Published functional studies demonstrate that this variant was reported to have SSADH enzyme activity of less than 1% relative to wild-type (Akaboshi et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30829465, 11243727, 20304328, 28664505, 14635103, 32395407, 33531951, 32093054, 32402538, 33203024, 32887777) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.0

M;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.6

D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MVP

0.98

MPC

1.1

ClinPred

0.98

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.96

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