rs118203982

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001080.3(ALDH5A1):c.612G>A(p.Trp204Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,918 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 stop_gained, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.50

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-24504871-G-A is Pathogenic according to our data. Variant chr6-24504871-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24504871-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.612G>A	p.Trp204Ter	stop_gained, splice_region_variant	4/10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1 linkuse as main transcript	c.612G>A	p.Trp204Ter	stop_gained, splice_region_variant	4/11		NP_733936.1
ALDH5A1	NM_001368954.1 linkuse as main transcript	c.612G>A	p.Trp204Ter	stop_gained, splice_region_variant	4/9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 linkuse as main transcript	c.612G>A	p.Trp204Ter	stop_gained, splice_region_variant	4/10	1	NM_001080.3	ENSP00000350191	P1	P51649-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251486

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000326

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency

Pathogenic:12

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with succinic semialdehyde dehydrogenase deficiency (MIM#271980). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to biallelic loss of function variants (gnomAD). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. NMD-predicted variants in this gene are well-reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported in multiple individuals with succinic semialdehyde dehydrogenase deficiency (ClinVar, PMID: 11243727, 14635103, 26964512). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	curation	Elsea Laboratory, Baylor College of Medicine	Mar 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The ALDH5A1 c.612G>A (p.Trp204Ter) variant is a stop-gained variant and is predicted to result in premature truncation of the protein. The p.Trp204Ter variant has been reported in three studies in which it is found in a total of ten individuals with succinic semialdehyde dehydrogenase (SSADH) deficiency, including in two who were homozygous for the variant, seven who carried the variant in a compound heterozygous state, and one who carried the variant in a heterozygous state where a second variant was not identified (Hogema et al. 2001; Akaboshi et al. 2003; Manrique Martin et al. 2018). The p.Trp204Ter variant was absent from 140 control chromosomes but is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. During prenatal evaluation of one fetus carrying the variant in a compound heterozygous state, 4-hydroxybutyric acid levels in the amniotic fluid were increased and SSADH activity was decreased in amniocytes and chorionic villi (Hogema et al. 2001). Based on the evidence and the potential impact of stop-gained variants, the p.Trp204Ter 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2018	The p.Trp204X variant in ALDH5A1 has been identified in homozygous state in 2 in dividuals and in compound heterozygous state in 5 individuals with succinic semi aldehyde dehydrogenase deficiency. It has also been identified in 11/ 126714 Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org/; dbSNP rs118203982). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. This variant has been reported in ClinVar (Variation ID: 13 57). This nonsense variant leads to a premature termination codon at position 20 4, which is predicted to lead to a truncated or absent protein. Loss of function of the ALDH5A1 gene is an established disease mechanism in autosomal recessive succinic semialdehyde dehydrogenase deficiency. In summary, the p.Trp204X meets criteria to be classified as pathogenic for succinic semialdehyde dehydrogenase deficiency in an autosomal recessive manner. ACMG/AMP criteria applied: PVS1, PM 3_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Dec 11, 2019	ACMG evidence PVS1, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Trp204*) in the ALDH5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH5A1 are known to be pathogenic (PMID: 14635103). This variant is present in population databases (rs118203982, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with succinic semialdehyde dehydrogenase deficiency (PMID: 11243727, 14635103). ClinVar contains an entry for this variant (Variation ID: 1357). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: ALDH5A1 c.612G>A (p.Trp204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 4.8e-05 in 251486 control chromosomes (gnomAD). c.612G>A has been reported in the literature in multiple bi-allelic individuals affected with Succinic Semialdehyde Dehydrogenase Deficiency (example: Akaboshi_2003). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 14635103). Eleven 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	Fulgent Genetics, Fulgent Genetics	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	Mar 03, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32238909, 32395407, 33393837, 32887777, 33679889, 25525159, 29431110, 11243727, 26964512, 14635103, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.92

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 12

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