GCH1

Chr 14ADAR

GTP cyclohydrolase 1

Also known as: DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1, HPABH4B

NCBI Gene: 2643 ENSG00000131979 UniProt: P30793 OMIM: 600225

The protein is GTP cyclohydrolase I, the rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis that converts GTP to 7,8-dihydroneopterin triphosphate, with BH4 serving as an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. Loss-of-function mutations cause dopa-responsive dystonia (autosomal dominant) and BH4-deficient hyperphenylalaninemia (autosomal recessive). The pathogenic mechanism involves loss of enzyme function leading to BH4 deficiency and subsequent impairment of dopamine and other neurotransmitter synthesis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.402 OMIM phenotypes

Clinical Summary— GCH1

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Gene-Disease Validity (ClinGen)

GTP cyclohydrolase I deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

126 unique Pathogenic / Likely Pathogenic· 242 VUS of 629 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GCH1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.40LOEUF

pLI 0.903

Z-score 2.93

OE 0.08 (0.03–0.40)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.52Z-score

OE missense 0.63 (0.53–0.76)

86 obs / 135.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.40)

0≤0.351.4

Missense OE?0.63 (0.53–0.76)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 1 / 11.9Missense obs/exp: 86 / 135.8Syn Z: -0.90

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGCH1-related dystoniaOTHERAD

definitiveGCH1-related GTP cyclohydrolase 1 deficiencyOTHERAR

This gene — mechanism propensity

0.4686th %ile

GOF

0.3292th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 56% of P/LP variants are LoF · LOEUF 0.40 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFStudy of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT51

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 17804835 ↗

ClinVar Variant Classifications

629 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic85

Likely Pathogenic41

VUS242

Likely Benign188

Benign30

Conflicting39

Pathogenic

Likely Pathogenic

242

VUS

188

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	20	12	0	85
Likely Pathogenic	18	21	2	0	41
VUS	4	186	50	2	242
Likely Benign	1	1	78	108	188
Benign	0	0	30	0	30
Conflicting	—				39
Total	76	228	172	110	625

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap GCH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →