GCLC

glutamate-cysteine ligase catalytic subunit

Basic information

Region (hg38): 6:53497341-53616970

Previous symbols: [ "GLCLC", "GLCL" ]

Links

ENSG00000001084 ∙ NCBI:2729 ∙ OMIM:606857 ∙ HGNC:4311 ∙ Uniprot:P48506 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• gamma-glutamylcysteine synthetase deficiency (Moderate), mode of inheritance: AR
• gamma-glutamylcysteine synthetase deficiency (Supportive), mode of inheritance: AR
• gamma-glutamylcysteine synthetase deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Gamma-glutamylcysteine synthetase deficiency	AR	Hematologic; Pharmacogenomic	Individuals have required exchange transfusion for infantile hyperbilirubinemia; Hemolysis-causing medications should be avoided; Supplementation (eg, with vitamins C or E) may be beneficial	Hematologic	5058793; 4852017; 2294991; 8634459; 10515893; 10733484; 12663448; 21657237

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GCLC gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GCLC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	23	2	26
missense			45			45
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	9	1	12
non coding			3	22	28	53
Total	0	0	50	45	30

Variants in GCLC

This is a list of pathogenic ClinVar variants found in the GCLC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-53498689-GGGCT-G			Benign (Nov 11, 2018)
6-53498761-T-C			Uncertain significance (May 17, 2022)
6-53498763-G-C		Gamma-glutamylcysteine synthetase deficiency	Uncertain significance (-)
6-53498796-T-C			Uncertain significance (May 04, 2022)
6-53498806-C-A		Inborn genetic diseases	Uncertain significance (Mar 29, 2022)
6-53498852-G-A			Likely benign (Aug 02, 2022)
6-53498879-C-A		Inborn genetic diseases	Uncertain significance (Aug 14, 2023)
6-53498883-T-G			Uncertain significance (Dec 16, 2019)
6-53498927-G-A			Likely benign (Jan 25, 2024)
6-53498927-G-C		Gamma-glutamylcysteine synthetase deficiency	Uncertain significance (Apr 11, 2023)
6-53498935-C-T			Uncertain significance (Feb 11, 2022)
6-53498975-C-T			Likely benign (Dec 21, 2023)
6-53498978-G-C			Benign (Jan 29, 2024)
6-53498986-C-T			Benign (Jan 29, 2024)
6-53499011-GT-G			Benign (Nov 11, 2018)
6-53499150-G-C			Benign (Jun 18, 2021)
6-53500030-A-C			Likely benign (Jul 11, 2022)
6-53500035-G-C			Likely benign (Jan 07, 2024)
6-53500115-G-A			Benign/Likely benign (Aug 17, 2023)
6-53500139-T-A			Likely benign (Nov 01, 2023)
6-53500179-G-T			Likely benign (Apr 06, 2022)
6-53500221-G-C			Benign (Jun 18, 2021)
6-53500228-T-C			Likely benign (Mar 27, 2022)
6-53500239-C-T			Likely benign (Jul 29, 2023)
6-53500253-A-G			Likely benign (Feb 17, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GCLC	protein_coding	protein_coding	ENST00000229416	16	119630

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.427	0.573	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.55	205	337	0.609	0.0000171	4216
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.000185	0.000185
European (Non-Finnish)	0.0000704	0.0000703
Middle Eastern	0.000109	0.000109
South Asian	0.0000654	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Gamma-glutamyl-transpeptidase deficiency;5-oxoprolinase deficiency;Gamma-Glutamyltransferase Deficiency;Glutathione Metabolism;Cysteine Metabolism;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Glutathione Synthetase Deficiency;Succinic semialdehyde dehydrogenase deficiency;Cystinosis, ocular nonnephropathic;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;5-Oxoprolinuria;Glutamate Metabolism;Glutathione metabolism;Trans-sulfuration and one carbon metabolism;Aryl Hydrocarbon Receptor;Apoptosis-related network due to altered Notch3 in ovarian cancer;Nuclear Receptors Meta-Pathway;NRF2 pathway;Transcriptional activation by NRF2;Photodynamic therapy-induced NFE2L2 (NRF2) survival signaling;One carbon metabolism and related pathways;Oxidative Stress;Glutathione conjugation;Phase II - Conjugation of compounds;Glutamate Glutamine metabolism;Biological oxidations;Metabolism;glutathione biosynthesis;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Arginine Proline metabolism;γ-glutamyl cycle;Glutathione synthesis and recycling (Consensus)

Recessive Scores

• pRec: 0.652

Intolerance Scores

• loftool: 0.456
• rvis_EVS: -0.47
• rvis_percentile_EVS: 23.43

Haploinsufficiency Scores

• pHI: 0.686
• hipred: Y
• hipred_score: 0.575
• ghis: 0.533

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.990

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gclc
• Phenotype: liver/biliary system phenotype; embryo phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: cysteine metabolic process;glutamate metabolic process;glutathione biosynthetic process;response to oxidative stress;aging;response to nutrient;apoptotic mitochondrial changes;response to heat;response to xenobiotic stimulus;response to hormone;response to activity;L-ascorbic acid metabolic process;negative regulation of protein ubiquitination;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;cellular response to insulin stimulus;cellular response to hepatocyte growth factor stimulus;negative regulation of apoptotic process;negative regulation of neuron apoptotic process;cellular response to fibroblast growth factor stimulus;response to human chorionic gonadotropin;cell redox homeostasis;negative regulation of transcription, DNA-templated;response to arsenic-containing substance;response to cadmium ion;regulation of blood vessel size;response to nitrosative stress;regulation of mitochondrial depolarization;response to interleukin-1;cellular response to mechanical stimulus;cellular response to glucose stimulus;cellular response to follicle-stimulating hormone stimulus;cellular response to thyroxine stimulus;negative regulation of hepatic stellate cell activation;negative regulation of extrinsic apoptotic signaling pathway
• Cellular component: cytosol;glutamate-cysteine ligase complex
• Molecular function: magnesium ion binding;glutamate-cysteine ligase activity;ATP binding;glutamate binding;ADP binding;protein heterodimerization activity;coenzyme binding