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UniProtKB/Swiss-Prot P30793: Variant p.Met221Thr

GTP cyclohydrolase 1
Gene: GCH1
Variant information

Variant position:  221
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Methionine (M) to Threonine (T) at position 221 (M221T, p.Met221Thr).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and hydrophobic (M) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In HPABH4B; intermediate phenotype presenting with dystonia and motor delay; compound heterozygote for an additional deletion.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  221
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  250
The length of the canonical sequence.

Location on the sequence:   GVGVVVEATHMCMVMRGVQK  M NSKTVTSTMLGVFREDPKTR
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         GVGVVVEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKTR

Mouse                         GVGVVIEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKTR

Rat                           GVGVVIEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKTR

Chicken                       GVGVVIEATHMCMVMRGVQKMNSKTATSTMLGVFREDPKTR

Caenorhabditis elegans        GVAVVIEASHMCMVMRGVQKINASTTTSCMLGVFRDDPKTR

Drosophila                    GVAVVVEGVHMCMVMRGVQKINSKTVTSTMLGVFRDDPKTR

Slime mold                    GVAVVIEASHMCMVMRGVQKPGASTVTSSVCGIFEKDSRTR

Baker's yeast                 GVAVVMEASHMCMVSRGIQKTGSSTVTSCMLGGFR-AHKTR

Fission yeast                 GVAVVMEATHMCMVMRGVEKPGSSTVTSSLTGIFQRSHKTR

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 250 GTP cyclohydrolase 1
Metal binding 212 – 212 Zinc
Alternative sequence 210 – 250 Missing. In isoform GCH-3.
Alternative sequence 210 – 233 HMCMVMRGVQKMNSKTVTSTMLGV -> KSNKYNKGLSPLLSSCHLFVAILK. In isoform GCH-4.
Alternative sequence 214 – 250 Missing. In isoform GCH-2.


Literature citations

Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.
Furukawa Y.; Kish S.J.; Bebin E.M.; Jacobson R.D.; Fryburg J.S.; Wilson W.G.; Shimadzu M.; Hyland K.; Trugman J.M.;
Ann. Neurol. 44:10-16(1998)
Cited for: VARIANTS HPABH4B ASP-108; THR-221 AND ARG-224;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.