GSS

protein-coding

glutathione synthetase

Gene summary

Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000178.4

Inheritance

ClinVar variants

P:54U:137B:146

Top phenotype

Glutathione synthetase deficiency

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr20:34,928,432-34,956,027

External References & Databases

Ensembl (ENSG00000100983)

Transcript & Mutation Effects

hg38 • Region Span ~27.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inherited glutathione synthetase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017909

Submitter: ClinGen

The relationship between GSS and glutathione synthetase deficiency was evaluated using the ClinGen Clinical Validity Framework as of April 20th, 2019. Glutathione is a tripeptide composed of glutamate, cysteine and glycine. It is present in in most mammalian cells and it is involved in several fundamental biological functions, including protection against oxidative damage (PMID 17397529). Glutathione synthetase deficiency is the most common disorder of glutathione metabolism. It is inherited in an autosomal recessive manner. In its most severe form, glutathione synthetase deficiency is characterized by hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system symptoms, and recurrent bacterial infections. However, milder cases, with only mild hemolytic anemia and normal 5-oxoproline levels have also been described (for reviews, see PMIDs 17397529 and 15990954). More than 50 families have been described worldwide (PMID 17397529). Variants in GSS, which encodes glutathione synthetase, were first reported in humans with this condition as early as 1996 (Shi et al, PMID 8896573). Data from 12 patients with 14 unique variants (missense, splicing, nonsense, frameshift, and exon duplication) from 7 publications were curated (Shi et al, 1996, PMID 8896573; Dahl et al, 1997, PMID 9215686; Al-Jishi et al, 1999; PMID 10450861; Li et al, 2015, PMID 25851806; Njålsson et al, 2003; PMID 14635114; Signolet et al, 2016, PMID 27581854; Xia et al, 2018, PMID 29340523). This gene-disease relationship is supported by the biochemical function of glutathione synthetase, resulting in glutathione deficiency and 5-oxoprolinuria in when the enzyme activity is deficient (Snoke et al, 1953; PMID 13061393; Richman et al, 1975, PMID 1112810), as well as functional studies (Ingle et al, 2018; PMID 30581542). In summary, GSS is definitively associated with autosomal recessive glutathione synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 26, 2019.

inherited glutathione synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017909

Submitter: PanelApp Australia

glutathione synthetase deficiency with 5-oxoprolinuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009947

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Glutathione synthetase deficiencyAR

Manifestation: Biochemical; Hematologic; Neurologic; Ophthalmologic

Intervention: Biochemical;Hematologic; Pharmacogenomic

Rationale: Medical therapy (eg, N-acetylcysteine, vitamin E), may improve outcomes, especially if administered early; Hemolysis-causing drugs should be avoided; Acidosis can be medically corrected

Refs: 13731008; 5901982; 5486400; 5476481; 481537; 3944259; 2502672; 1770788; 1986110; 7937585; 8896573; 11445798; 15717202; 15990954; 16435214; 17206463; 17479648; 19728142; 21988557

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GSS variants in ClinVar

11 Conditions Cataloged

Glutathione synthetase deficiency with 5-oxoprolinuriaTotal: 300

not providedTotal: 123

Inborn genetic diseasesTotal: 84

Inherited glutathione synthetase deficiencyTotal: 53

not specifiedTotal: 35

Glutathione synthetase deficiency without 5-oxoprolinuriaTotal: 25

GSS-related disorderTotal: 8

GSS-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000178.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	132 clinvar	1 clinvar	136
missense	2 clinvar	7 clinvar	127 clinvar	12 clinvar	1 clinvar	149
nonsense	8 clinvar	11 clinvar				19
start loss		1 clinvar				1
frameshift	7 clinvar	9 clinvar	3 clinvar			19
splice donor/acceptor (+/-2bp)		9 clinvar	4 clinvar			13
Total	17	37	137	144	2	337

Highest pathogenic variant AF is 0.00011462475

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000178.4	RefSeq	NP_000169.1	12	MANE Select
ENST00000651619.1	Ensembl	ENSP00000498303.1	12	MANE Select
NM_001322494.1	RefSeq	NP_001309423.1	12	Standard
NM_001322495.1	RefSeq	NP_001309424.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glutathione metabolism - Homo sapiens (human)
Cysteine and methionine metabolism - Homo sapiens (human)
Ferroptosis - Homo sapiens (human)
2-Hydroxyglutric Aciduria (D And L Form)
Gamma-glutamyl-transpeptidase deficiency

Biological Process

cellular amino acid metabolic process
glutathione biosynthetic process
response to oxidative stress
nervous system development
aging

Molecular Function

magnesium ion binding
glutathione synthase activity
protein binding
ATP binding
glycine binding

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216951
Coding exons: 12
Length: 27385
Individuals with no LoFs: 125641
Homozygous LoFs: 0
Heterozygous LoFs: 107
Defined: 125748
p: 0.000426

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.774	227	262	0.865	0.0000160	3049
Missense (PolyPhen)		88	100.51	0.87551		1197
Synonymous	1.11	93	108	0.864	0.00000625	988
Loss of Function	2.43	14	27.9	0.502	0.00000176	282

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.0045	0.0045	notable
East Asian	0.00049	0.00049	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.00016	0.00016	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Glutathione synthetase deficiency (GSS deficiency) [MIM:266130]: Severe form characterized by an increased rate of hemolysis and defective function of the central nervous system. {ECO:0000269|PubMed:27581854, ECO:0000269|PubMed:8896573, ECO:0000269|PubMed:9215686}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glutathione synthetase deficiency of erythrocytes (GLUSYNDE) [MIM:231900]: Mild form causing hemolytic anemia. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.328

Intolerance Scores

LoFtool: 0.256
RVIS EVS: -0.56
RVIS percentile EVS: 19.73

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.665

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium