GCH1

GTP cyclohydrolase 1, the group of MicroRNA protein coding host genes

Basic information

Region (hg38): 14:54842007-54902826

Previous symbols: [ "GCH", "DYT5", "DYT14" ]

Links

ENSG00000131979 ∙ NCBI:2643 ∙ OMIM:600225 ∙ HGNC:4193 ∙ Uniprot:P30793 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the GCH1 gene.

• Dystonia 5;GTP cyclohydrolase I deficiency (118 variants)
• not provided (115 variants)
• GTP cyclohydrolase I deficiency;Dystonia 5 (109 variants)
• Dystonia 5 (98 variants)
• GTP cyclohydrolase I deficiency (79 variants)
• not specified (10 variants)
• Inborn genetic diseases (8 variants)
• Dopa-responsive dystonia (8 variants)
• Dystonia 5;GTP cyclohydrolase I deficiency with hyperphenylalaninemia (6 variants)
• Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive (4 variants)
• Dystonic disorder (2 variants)
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia (2 variants)
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia;Dystonia 5 (1 variants)
• Abnormal central motor function (1 variants)
• Intellectual disability;Seizure (1 variants)
• 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (1 variants)
• GCH1-related condition (1 variants)
• See cases (1 variants)
• 6 conditions (1 variants)
• Intellectual disability (1 variants)
• Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (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				42		42
missense	4	17	107	1		129
nonsense	10	2	1			13
start loss	3					3
frameshift	15	5	1			21
inframe indel	1	1	2			4
splice donor/acceptor (+/-2bp)	13	3				16
splice region		1	8	5		14
non coding			36	38	27	101
Total	46	28	147	81	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;GTP cyclohydrolase I deficiency with hyperphenylalaninemia • Dystonia 5	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		Dystonia 5 • GTP cyclohydrolase I deficiency	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: gnomAD

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: dbNSFP

• 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