Gamma-glutamylcysteine synthetase deficiency

Summary

Gamma-glutamylcysteine synthetase deficiency (MONDO:0009259) is a disease caused by GCLC (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GCLC (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 34
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001878	Hemolytic anemia	Obligate (100%)
HP:0002503	Spinocerebellar tract degeneration	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001923	Reticulocytosis	Occasional (5-29%)
HP:0010522	Dyslexia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	gamma-glutamylcysteine synthetase deficiency
Mondo ID	MONDO:0009259
MeSH	C565557
OMIM	230450
Orphanet	33574
DOID	DOID:0111681
SNOMED CT	36799008
UMLS	C1856603
MedGen	347272
GARD	0016631
Is cancer (heuristic)	no

Also known as: anemia, congenital, nonspherocytic hemolytic, 7 · gamma-glutamylcysteine synthetase deficiency, hemolytic anaemia due to · gamma-glutamylcysteine synthetase deficiency, hemolytic anemia due to · glutamate-cysteine ligase deficiency · hemolytic anaemia due to gamma-glutamylcysteine synthetase deficiency · inborn error of glutamate-cysteine ligase activity · inborn glutamate-cysteine ligase activity disorder · rare inborn error of glutamate-cysteine ligase activity

Data availability: 34 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › gamma-glutamylcysteine synthetase deficiency

Related subtypes (9): anemia, nonspherocytic hemolytic, glutathione synthetase deficiency without 5-oxoprolinuria, non-spherocytic hemolytic anemia due to hexokinase deficiency, hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency, pyruvate kinase deficiency of red cells, hemolytic anemia due to adenylate kinase deficiency, hemolytic anemia due to glucophosphate isomerase deficiency, hemolytic anemia due to glutathione reductase deficiency, hemolytic anemia due to erythrocyte adenosine deaminase overproduction

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3363108	NM_001498.4(GCLC):c.473C>T (p.Pro158Leu)	GCLC	Pathogenic	no assertion criteria provided
3958	NM_001498.4(GCLC):c.1109A>T (p.His370Leu)	GCLC	Pathogenic	no assertion criteria provided
2428754	NM_001498.4(GCLC):c.447-3T>C	GCLC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546080	NM_001498.4(GCLC):c.514T>A (p.Ser172Thr)	GCLC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448042	NM_001498.4(GCLC):c.1499G>A (p.Gly500Asp)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1676021	NM_001498.4(GCLC):c.177T>G (p.Asp59Glu)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2069479	NM_001498.4(GCLC):c.1531G>A (p.Ala511Thr)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2084290	NM_001498.4(GCLC):c.1427G>T (p.Arg476Ile)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2163774	NM_001498.4(GCLC):c.775A>G (p.Ile259Val)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432084	NM_001498.4(GCLC):c.346G>A (p.Glu116Lys)	GCLC	Uncertain significance	criteria provided, single submitter
2432085	NM_001498.4(GCLC):c.1004A>G (p.Tyr335Cys)	GCLC	Uncertain significance	criteria provided, single submitter
2432086	NM_001498.4(GCLC):c.1280G>C (p.Arg427Pro)	GCLC	Uncertain significance	criteria provided, single submitter
2432087	NM_001498.4(GCLC):c.1106A>G (p.Gln369Arg)	GCLC	Uncertain significance	criteria provided, single submitter
2432088	NM_001498.4(GCLC):c.196C>T (p.Arg66Trp)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432089	NM_001498.4(GCLC):c.364G>C (p.Ala122Pro)	GCLC	Uncertain significance	criteria provided, single submitter
2432090	NM_001498.4(GCLC):c.1478-3C>G	GCLC	Uncertain significance	criteria provided, single submitter
2594446	NM_001498.4(GCLC):c.1791G>T (p.Met597Ile)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2663934	NM_001498.4(GCLC):c.1907C>G (p.Ser636Cys)	GCLC	Uncertain significance	criteria provided, single submitter
2689118	NM_001498.4(GCLC):c.1066G>A (p.Glu356Lys)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689119	NM_001498.4(GCLC):c.935G>A (p.Arg312Gln)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689120	NM_001498.4(GCLC):c.94C>T (p.His32Tyr)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689121	NM_001498.4(GCLC):c.1743C>G (p.Ile581Met)	GCLC	Uncertain significance	criteria provided, single submitter
2689122	NM_001498.4(GCLC):c.1267A>G (p.Arg423Gly)	GCLC	Uncertain significance	criteria provided, single submitter
2689123	NM_001498.4(GCLC):c.1538A>T (p.Glu513Val)	GCLC	Uncertain significance	criteria provided, single submitter
2896667	NM_001498.4(GCLC):c.1520G>T (p.Ser507Ile)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
3853223	NM_001498.4(GCLC):c.110T>C (p.Val37Ala)	GCLC	Uncertain significance	criteria provided, multiple submitters, no conflicts
4078750	NM_001498.4(GCLC):c.754-3C>T	GCLC	Uncertain significance	criteria provided, single submitter
4078751	NM_001498.4(GCLC):c.725G>C (p.Gly242Ala)	GCLC	Uncertain significance	criteria provided, single submitter
4078752	NM_001498.4(GCLC):c.53A>T (p.His18Leu)	GCLC	Uncertain significance	criteria provided, single submitter
4078753	NM_001498.4(GCLC):c.1021G>A (p.Glu341Lys)	GCLC	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GCLC	Strong	Autosomal recessive	gamma-glutamylcysteine synthetase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCLC	Orphanet:33574	Glutamate-cysteine ligase deficiency
GCLC	Orphanet:586	Cystic fibrosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCLC	HGNC:4311	ENSG00000001084	P48506	Glutamate–cysteine ligase catalytic subunit	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCLC	Glutamate–cysteine ligase catalytic subunit	Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCLC	Enzyme (other)	yes	6.3.2.2	GCS, Gln_synth/guanido_kin_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCLC	291	ubiquitous	marker	bronchial epithelial cell, right uterine tube, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCLC	1,928

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GCLC	P48506	93.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GCLC causes HAGGSD	1	5710.0×	5e-04	GCLC
Glutathione synthesis and recycling	1	951.7×	0.002	GCLC
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	543.8×	0.002	GCLC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to human chorionic gonadotropin	1	8426.0×	0.001	GCLC
cellular response to thyroxine stimulus	1	8426.0×	0.001	GCLC
negative regulation of hepatic stellate cell activation	1	8426.0×	0.001	GCLC
obsolete cysteine metabolic process	1	4213.0×	0.002	GCLC
response to nitrosative stress	1	4213.0×	0.002	GCLC
regulation of mitochondrial depolarization	1	2808.7×	0.002	GCLC
glutathione biosynthetic process	1	1532.0×	0.002	GCLC
L-ascorbic acid metabolic process	1	1532.0×	0.002	GCLC
cellular response to follicle-stimulating hormone stimulus	1	1404.3×	0.002	GCLC
response to arsenic-containing substance	1	1203.7×	0.002	GCLC
glutamate metabolic process	1	1123.5×	0.002	GCLC
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.002	GCLC
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	1053.2×	0.002	GCLC
response to cadmium ion	1	732.7×	0.003	GCLC
blood vessel diameter maintenance	1	624.1×	0.004	GCLC
cellular response to fibroblast growth factor stimulus	1	543.6×	0.004	GCLC
response to interleukin-1	1	510.7×	0.004	GCLC
response to hormone	1	432.1×	0.004	GCLC
response to heat	1	421.3×	0.004	GCLC
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.004	GCLC
cell redox homeostasis	1	343.9×	0.005	GCLC
response to activity	1	324.1×	0.005	GCLC
response to nutrient	1	295.6×	0.005	GCLC
negative regulation of protein ubiquitination	1	285.6×	0.005	GCLC
cellular response to glucose stimulus	1	267.5×	0.005	GCLC
cellular response to mechanical stimulus	1	216.1×	0.006	GCLC
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	210.7×	0.006	GCLC
cellular response to insulin stimulus	1	170.2×	0.007	GCLC
response to oxidative stress	1	130.6×	0.009	GCLC
negative regulation of neuron apoptotic process	1	110.9×	0.010	GCLC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCLC	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BUTHIONINE SULFOXIMINE	1	GCLC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GCLC	14	Binding:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCLC	6.3.2.2	glutamate-cysteine ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BUTHIONINE SULFOXIMINE	1	GCLC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GCLC
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.