rs375628463

Positions:

chr6-24515243-G-A

Variant summary

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

The NM_001080.3(ALDH5A1):c.803G>A(p.Gly268Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,390 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.81

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, 0.982

PP5

Variant 6-24515243-G-A is Pathogenic according to our data. Variant chr6-24515243-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 235512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24515243-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH5A1	NM_001080.3 linkuse as main transcript	c.803G>A	p.Gly268Glu	missense_variant	5/10	ENST00000357578.8
ALDH5A1	NM_170740.1 linkuse as main transcript	c.842G>A	p.Gly281Glu	missense_variant	6/11
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.727-5158G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.803G>A	p.Gly268Glu	missense_variant	5/10	1	NM_001080.3	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

151558

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251478

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000249

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000858

AC:

AN:

151558

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73956

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:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	The ALDH5A1 c.803G>A (p.Gly268Glu) missense variant, also known as the p.Gly281Glu variant, has been reported in a compound heterozygous state in five unrelated individuals with succinic semialdehyde dehydrogenase (SSADH) deficiency (Hogema et al. 2001; Akaboshi et al. 2003). The p.Gly268Glu variant was absent from 140 control chromosomes and is reported at a frequency of 0.000145 in the Latino population of the Genome Aggregation Database. HEK293 cells expressing the p.Gly268Glu variant demonstrated <1% SSADH activity compared to wild type (Akaboshi et al. 2003). Based on the evidence, the p.Gly268Glu variant is classified as pathogenic for succinic semialdehyde dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 268 of the ALDH5A1 protein (p.Gly268Glu). This variant is present in population databases (rs375628463, gnomAD 0.01%). This missense change has been observed in individual(s) with succinic semialdehyde dehydrogenase deficiency (PMID: 11243727, 14635103, 27104484). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 235512). 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. Experimental studies have shown that this missense change affects ALDH5A1 function (PMID: 14635103). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Elsea Laboratory, Baylor College of Medicine	Mar 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Oct 28, 2020	The p.Gly268Glu variant in the ALDH5A1 gene has been previously reported in 7 unrelated individuals with succinic semialdehyde dehydrogenase deficiency (Akaboshi, et al., 2003, Hogema et al., 2001; Horvath et al., 2016). All affected individuals were compound heterozygotes. This variant was determined to be in trans with a disease-associated variant (p.Trp204, p.Arg412), consistent with autosomal recessive inheritance. The presence of this variant with a likely disease causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has also been identified in 24/282406 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies of the p.Gly268Glu variant suggest a deleterious effect to the protein that is sufficient to be disease-causing (Akaboshi et al., 2003; Hogema et al., 2001). Computational tools predict that the p.Gly268Glu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Gly268Glu variant as pathogenic for autosomal recessive succinic semialdehyde dehydrogenase deficiency based on the information above. [ACMG evidence codes used: PS4; PS3_Moderate; PM2; PM3; PP3] -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2023	Variant summary: ALDH5A1 c.803G>A (p.Gly268Glu) 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 8.7e-05 in 251478 control chromosomes (gnomAD). c.803G>A has been reported in the literature in individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (example: Akaboshi_2003). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Akaboshi_ALDH5A1_HumMutat_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11243727, 14635103). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 19, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2024	Published functional studies demonstrate that G268E results in loss of SSADH enzymatic activity (PMID: 14635103, 32402538); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27104484, 25525159, 20174634, 19300440, 37962671, 31515079, 31440721, 32402538, 23825041, 26964512, 20804942, 11243727, 14635103, 25558043, 33203024) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2017

- -

ALDH5A1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The ALDH5A1 c.803G>A variant is predicted to result in the amino acid substitution p.Gly268Glu. This variant has been reported in the compound heterozygous state in several individuals with succinic semialdehyde dehydrogenase deficiency (SSADH) (Hogema et al. 2001. PubMed ID: 11243727; Horvath et al. 2016. PubMed ID: 27104484; Latzer et al. 2023. PubMed ID: 37962671). Functional studies using HEK293 cells indicated that the p.Gly268Glu decreased succinate semialdehyde dehydrogenase activity to less than 1% (Akaboshi et al. 2003. PubMed ID: 14635103). In silico structural modeling predicts the Gly268 residue maintains stability of the alpha-helix, which is a crucial component of NAD+ binding. This variant loosens critical interactions necessary for proper binding, negatively affecting protein function and stability (Latzer et al. 2023. PubMed ID: 37962671). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.5

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MVP

0.98

MPC

1.1

ClinPred

0.98

GERP RS

5.3

Varity_R

0.99

gMVP

0.95

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