GCH1
GTP cyclohydrolase 1, the group of MicroRNA protein coding host genes
Basic information
Region (hg38): 14:54842008-54902826
Previous symbols: [ "GCH", "DYT5", "DYT14" ]
Links
Phenotypes
GenCC
Source:
- GTP cyclohydrolase I deficiency with hyperphenylalaninemia (Definitive), mode of inheritance: AR
- dystonia 5 (Definitive), mode of inheritance: AD
- dystonia 5 (Strong), mode of inheritance: AD
- dystonia 5 (Strong), mode of inheritance: AR
- GTP cyclohydrolase I deficiency with hyperphenylalaninemia (Strong), mode of inheritance: AR
- dystonia 5 (Definitive), mode of inheritance: AD
- GTP cyclohydrolase I deficiency with hyperphenylalaninemia (Supportive), mode of inheritance: AR
- dystonia 5 (Supportive), mode of inheritance: AD
- GTP cyclohydrolase I deficiency (Definitive), mode of inheritance: AD
- dystonia 5 (Strong), mode of inheritance: AD
- GTP cyclohydrolase I deficiency with hyperphenylalaninemia (Strong), mode of inheritance: AR
- GTP cyclohydrolase I deficiency (Definitive), mode of inheritance: Semidominant
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Hyperphenylalaninemia, BH4-deficient, B; Dystonia, dopa-responsive | AD/AR | Biochemical | In Hyperphenylalaninemia, BH4-deficient, B, medical therapy (eg, BH-4, 5-HT, L-dopa) may be beneficial; In Dopa-responsive dystonia, which may not be easily clinically recognizable early, L-dopa can be effective | Biochemical; Neurologic | 942621; 945938; 6734669; 3762960; 3822637; 3400489; 3041760; 2296384; 1899474; 8163996; 7874165; 7869202; 7730309; 9667588; 10208576; 10987649; 11113234; 11346370; 12084887; 12552057; 15753436; 16908750; 17111153; 20301681 |
ClinVar
This is a list of variants' phenotypes submitted to
- GTP cyclohydrolase I deficiency;Dystonia 5 (30 variants)
- not provided (15 variants)
- Dystonia 5 (13 variants)
- Dystonia 5;GTP cyclohydrolase I deficiency (12 variants)
- GTP cyclohydrolase I deficiency (3 variants)
- Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive (1 variants)
- Dystonic disorder (1 variants)
- Inborn genetic diseases (1 variants)
- GTP cyclohydrolase I deficiency with hyperphenylalaninemia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the GCH1 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 | 88 | 90 | ||||
| missense | 17 | 129 | 153 | |||
| nonsense | 11 | 14 | ||||
| start loss | 3 | |||||
| frameshift | 15 | 21 | ||||
| inframe indel | 5 | |||||
| splice donor/acceptor (+/-2bp) | 14 | 18 | ||||
| splice region | 9 | 7 | 16 | |||
| non coding | 35 | 67 | 27 | 130 | ||
| Total | 52 | 29 | 170 | 156 | 27 |
Highest pathogenic variant AF is 0.00000658
Variants in GCH1
This is a list of pathogenic ClinVar variants found in the GCH1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 14-54842102-A-G | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign (Jan 12, 2018) | ||
| 14-54842110-T-C | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Jan 12, 2018) | ||
| 14-54842162-T-C | Dystonia 5 • GTP cyclohydrolase I deficiency | Uncertain significance (Jan 13, 2018) | ||
| 14-54842193-T-G | Dystonia 5 • GTP cyclohydrolase I deficiency | Uncertain significance (Jan 12, 2018) | ||
| 14-54842298-G-A | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Jan 13, 2018) | ||
| 14-54842389-T-G | GTP cyclohydrolase I deficiency • Dystonia 5 • Dystonia 5;GTP cyclohydrolase I deficiency with hyperphenylalaninemia | Uncertain significance (Sep 01, 2021) | ||
| 14-54842538-C-A | Dopa-responsive dystonia • GTP cyclohydrolase I deficiency | Likely benign (Jun 14, 2016) | ||
| 14-54842544-T-C | Dystonia 5 • GTP cyclohydrolase I deficiency | Uncertain significance (Jan 12, 2018) | ||
| 14-54842552-A-AAT | GTP cyclohydrolase I deficiency • Dopa-responsive dystonia | Likely benign (Jun 14, 2016) | ||
| 14-54842723-T-C | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Apr 28, 2017) | ||
| 14-54842734-T-G | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Jan 13, 2018) | ||
| 14-54842760-G-A | Dystonia 5 • GTP cyclohydrolase I deficiency | Uncertain significance (Jan 13, 2018) | ||
| 14-54842787-G-A | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign (Aug 30, 2018) | ||
| 14-54842834-G-A | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign (Jul 05, 2018) | ||
| 14-54842841-G-C | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign/Likely benign (Jan 13, 2018) | ||
| 14-54842875-C-T | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign (Jul 05, 2018) | ||
| 14-54842887-G-C | Dystonia 5 • GTP cyclohydrolase I deficiency | Benign/Likely benign (Jan 13, 2018) | ||
| 14-54842895-T-A | GTP cyclohydrolase I deficiency • Dystonia 5 | Benign/Likely benign (Jan 13, 2018) | ||
| 14-54842959-C-T | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Jan 12, 2018) | ||
| 14-54842960-G-GAT | Dopa-responsive dystonia • GTP cyclohydrolase I deficiency | Benign (Jul 05, 2018) | ||
| 14-54842973-C-T | Dystonia 5 • GTP cyclohydrolase I deficiency | Conflicting classifications of pathogenicity (Jan 12, 2018) | ||
| 14-54842975-T-C | GTP cyclohydrolase I deficiency • Dystonia 5 | Uncertain significance (Mar 16, 2018) | ||
| 14-54842984-G-A | GTP cyclohydrolase I deficiency • Dystonia 5 • Dystonia 5;GTP cyclohydrolase I deficiency with hyperphenylalaninemia | Uncertain significance (Sep 07, 2021) | ||
| 14-54843007-G-A | GTP cyclohydrolase I deficiency • Dystonia 5 | Conflicting classifications of pathogenicity (Jan 13, 2018) | ||
| 14-54843082-T-G | Dystonia 5 • GTP cyclohydrolase I deficiency | Uncertain significance (Jan 13, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| GCH1 | protein_coding | protein_coding | ENST00000491895 | 6 | 60845 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.903 | 0.0969 | 124500 | 0 | 2 | 124502 | 0.00000803 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.52 | 86 | 136 | 0.633 | 0.00000723 | 1623 |
| Missense in Polyphen | 19 | 53.766 | 0.35338 | 617 | ||
| Synonymous | -0.901 | 59 | 50.8 | 1.16 | 0.00000257 | 487 |
| Loss of Function | 2.93 | 1 | 11.9 | 0.0838 | 6.90e-7 | 129 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000180 | 0.0000180 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown. {ECO:0000269|PubMed:12176133, ECO:0000269|PubMed:16338639, ECO:0000269|PubMed:17057711, ECO:0000269|PubMed:8068008, ECO:0000269|PubMed:9445252}.;
- Disease
- DISEASE: Hyperphenylalaninemia, BH4-deficient, B (HPABH4B) [MIM:233910]: A disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia. {ECO:0000269|PubMed:7501255, ECO:0000269|PubMed:9667588}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dystonia, dopa-responsive (DRD) [MIM:128230]: A form of dystonia that responds to L-DOPA treatment without side effects. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DRD typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and exercise. {ECO:0000269|PubMed:10076897, ECO:0000269|PubMed:10208576, ECO:0000269|PubMed:10582612, ECO:0000269|PubMed:10825351, ECO:0000269|PubMed:10987649, ECO:0000269|PubMed:11113234, ECO:0000269|PubMed:12391354, ECO:0000269|PubMed:17101830, ECO:0000269|PubMed:7501255, ECO:0000269|PubMed:7874165, ECO:0000269|PubMed:8852666, ECO:0000269|PubMed:8957022, ECO:0000269|PubMed:9120469, ECO:0000269|PubMed:9328244, ECO:0000269|PubMed:9778264}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Folate biosynthesis - Homo sapiens (human);Sepiapterin reductase deficiency;Segawa syndrome;Pterine Biosynthesis;Dopa-responsive dystonia;Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency;Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps);Hyperphenylalaninemia due to dhpr-deficiency;tetrahydrobiopterin <i>de novo</i> biosynthesis;Folate metabolism;Metabolism;Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation;Metabolism of cofactors;Metabolism of vitamins and cofactors;Purine nucleotides nucleosides metabolism
(Consensus)
Recessive Scores
- pRec
- 0.757
Intolerance Scores
- loftool
- 0.0278
- rvis_EVS
- -0.1
- rvis_percentile_EVS
- 46.2
Haploinsufficiency Scores
- pHI
- 0.292
- hipred
- Y
- hipred_score
- 0.825
- ghis
- 0.576
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Gch1
- Phenotype
- homeostasis/metabolism 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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);
Gene ontology
- Biological process
- tetrahydrobiopterin biosynthetic process;nitric oxide biosynthetic process;regulation of blood pressure;positive regulation of heart rate;regulation of lung blood pressure;response to lipopolysaccharide;response to interferon-gamma;response to tumor necrosis factor;7,8-dihydroneopterin 3'-triphosphate biosynthetic process;vasodilation;dopamine biosynthetic process;pteridine-containing compound biosynthetic process;negative regulation of blood pressure;tetrahydrofolate biosynthetic process;response to pain;neuromuscular process controlling posture;positive regulation of nitric-oxide synthase activity;cofactor metabolic process;protein homooligomerization;protein heterooligomerization;regulation of removal of superoxide radicals
- Cellular component
- nucleus;nucleoplasm;cytoplasm;cytosol;cytoplasmic vesicle;nuclear membrane;protein-containing complex;neuron projection terminus
- Molecular function
- GTPase activity;GTP cyclohydrolase I activity;calcium ion binding;protein binding;GTP binding;zinc ion binding;GTP-dependent protein binding;translation initiation factor binding;protein homodimerization activity;coenzyme binding;mitogen-activated protein kinase binding