GCLC
protein-codingglutamate-cysteine ligase catalytic subunit
Gene summary
Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate-limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.[provided by RefSeq, Oct 2010]
- GLCLC
- GLCL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~119.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009061
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009259
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009259
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009259
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009259
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic; Pharmacogenomic
Rationale: Individuals have required exchange transfusion for infantile hyperbilirubinemia; Hemolysis-causing medications should be avoided; Supplementation (eg, with vitamins C or E) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GCLC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001498.4. 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 | 1 | 43 | 44 | |||
| missense | 2 | 1 | 98 | 4 | 105 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 2 | 1 | 109 | 47 | 0 | 159 |
Highest pathogenic variant AF is 0.000001372742
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001489.1 | 16 | MANE Select | |
| Ensembl | ENSP00000497574.1 | 16 | MANE Select | |
| RefSeq | NP_001184044.1 | 15 | Standard | |
| Ensembl | ENSP00000421228.1 | 2 | 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)
- Beta-mercaptolactate-cysteine disulfiduria
- 2-Hydroxyglutric Aciduria (D And L Form)
Biological Process
- cysteine metabolic process
- glutamate metabolic process
- glutathione biosynthetic process
- response to oxidative stress
- aging
Molecular Function
- magnesium ion binding
- glutamate-cysteine ligase activity
- ATP binding
- glutamate binding
- ADP binding
Cellular Component
- cytosol
- glutamate-cysteine ligase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000229416
- Coding exons
- 16
- Length
- 119630
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125748
- p
- 0.0000676
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.55 | 205 | 337 | 0.609 | 0.0000171 | 4216 |
| Missense (PolyPhen) | 48 | 123.76 | 0.38785 | 1543 | ||
| Synonymous | 0.587 | 115 | 123 | 0.933 | 0.00000617 | 1168 |
| Loss of Function | 4.33 | 8 | 36.0 | 0.222 | 0.00000207 | 428 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.000070 | 0.000070 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency (HAGGSD) [MIM:230450]: A disease characterized by hemolytic anemia, glutathione deficiency, myopathy, late-onset spinocerebellar degeneration, and peripheral neuropathy. {ECO:0000269|PubMed:10515893, ECO:0000269|PubMed:10733484, ECO:0000269|PubMed:12663448}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.652
Intolerance Scores
- LoFtool
- 0.456
- RVIS EVS
- -0.47
- RVIS percentile EVS
- 23.43
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.990
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |