6-24504871-G-A

Variant names:

• chr6-24504871-G-A
• rs118203982
• NM_001080.3:c.612G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001080.3(ALDH5A1):​c.612G>A​(p.Trp204*) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.50
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• succinic semialdehyde dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-24504871-G-A is Pathogenic according to our data. Variant chr6-24504871-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.612G>A	p.Trp204*	stop_gained splice_region	Exon 4 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.612G>A	p.Trp204*	stop_gained splice_region	Exon 4 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.612G>A	p.Trp204*	stop_gained splice_region	Exon 4 of 9	NP_001355883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.612G>A	p.Trp204*	stop_gained splice_region	Exon 4 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.612G>A	p.Trp204*	stop_gained splice_region	Exon 4 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.528G>A	p.Trp176*	stop_gained splice_region	Exon 3 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152170 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251486 AF XY: 0.0000515

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 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.: 0 Cov.: 32 AF XY: 0.000232 AC XY: 169 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000326 AC: 363 AN: 1111892

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Succinate-semialdehyde dehydrogenase deficiency Pathogenic:13

Sep 11, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 08, 2021

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jun 17, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: 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); Variant is present in gnomAD <0.01 for a recessive condition (v4: 401 heterozygote(s), 0 homozygote(s)); 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); Other NMD-predicted variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with autosomal recessive disease; Loss of function is a known mechanism of disease in this gene and is associated with succinic semialdehyde dehydrogenase deficiency (MIM#271980); Variants in this gene are known to have variable expressivity (OMIM).

Aug 24, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 22, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 11, 2019

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG evidence PVS1, PM3, PP5

May 29, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 05, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 07, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALDH5A1 c.612G>A (p.Trp204*) variant has been reported in at least 10 individuals affected with succinic semialdehyde dehydrogenase deficiency. Of those individuals, eight were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and two individuals were homozygous for the variant (Acaboshi S et al., PMID: 14635103; Hogema BM et al., PMID: 11243727; Martin GM et al., PMID: 26964512). This variant has been reported in the ClinVar database as a germline pathogenic variant by fourteen submitters. This variant is only observed in 13/282878 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Molecular Genetics Lab, CHRU Brest

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Mar 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Feb 09, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		9.5
Vest4		0.92
GERP RS		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118203982; hg19: chr6-24505099; COSMIC: COSV62374378;