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UniProtKB/Swiss-Prot P07101: Variant p.Gly414Arg

Tyrosine 3-monooxygenase
Gene: TH
Variant information

Variant position:  414
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 Glycine (G) to Arginine (R) at position 414 (G414R, p.Gly414Arg).
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 glycine (G) to large size and basic (R)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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:  Segawa syndrome autosomal recessive (ARSEGS) [MIM:605407]: A form of DOPA-responsive dystonia presenting in infancy or early childhood. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Some cases present with parkinsonian symptoms in infancy. Unlike all other forms of dystonia, it is an eminently treatable condition, due to a favorable response to L-DOPA. {ECO:0000269|PubMed:10585338, ECO:0000269|PubMed:11196107, ECO:0000269|PubMed:11246459, ECO:0000269|PubMed:15505183, ECO:0000269|PubMed:15747353, ECO:0000269|PubMed:16049992, ECO:0000269|PubMed:17696123, ECO:0000269|PubMed:18058633, ECO:0000269|PubMed:18554280, ECO:0000269|PubMed:19491146, ECO:0000269|PubMed:20056467, ECO:0000269|PubMed:20430833, ECO:0000269|PubMed:21940685, ECO:0000269|PubMed:22264700, ECO:0000269|PubMed:22815559, ECO:0000269|PubMed:23762320, ECO:0000269|PubMed:23939262, ECO:0000269|PubMed:24753243, ECO:0000269|PubMed:7814018, ECO:0000269|PubMed:8528210, ECO:0000269|PubMed:8817341, ECO:0000269|PubMed:9613851, ECO:0000269|PubMed:9703425}. 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 ARSEGS; loss of over 80% of tyrosine hydroxylase activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  414
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  528
The length of the canonical sequence.

Location on the sequence:   IEKLSTLYWFTVEFGLCKQN  G EVKAYGAGLLSSYGELLHCL
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                         IEKLSTLYWFTVEFGLCKQNGEVKAYGAGLLSSYGELLHCL

                              IEKLSTLYWFTVEFGLCKQNGEVKAYGAGLLSSYGELLHSL

Mouse                         IEKLSTVYWFTVEFGLCKQNGELKAYGAGLLSSYGELLHSL

Rat                           IEKLSTVYWFTVEFGLCKQNGELKAYGAGLLSSYGELLHSL

Bovine                        IEKLSTLYWFTVEFGLCKQNGEVKAYGAGLLSSYGELLHSL

Caenorhabditis elegans        IEKLSTVYWFIVEFGLCKEDGKLKAIGAGLLSAYGELMHAC

Drosophila                    IEKLSTVYWFTVEFGLCKEHGQIKAYGAGLLSSYGELLHAI

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 – 528 Tyrosine 3-monooxygenase
Metal binding 406 – 406 Iron


Literature citations

Tyrosine hydroxylase deficiency presenting with a biphasic clinical course.
Giovanniello T.; Leuzzi V.; Carducci C.; Carducci C.; Sabato M.L.; Artiola C.; Santagata S.; Pozzessere S.; Antonozzi I.;
Neuropediatrics 38:213-215(2007)
Cited for: VARIANTS ARSEGS ARG-414 AND GLN-510;

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia.
Clot F.; Grabli D.; Cazeneuve C.; Roze E.; Castelnau P.; Chabrol B.; Landrieu P.; Nguyen K.; Ponsot G.; Abada M.; Doummar D.; Damier P.; Gil R.; Thobois S.; Ward A.J.; Hutchinson M.; Toutain A.; Picard F.; Camuzat A.; Fedirko E.; San C.; Bouteiller D.; LeGuern E.; Durr A.; Vidailhet M.; Brice A.;
Brain 132:1753-1763(2009)
Cited for: VARIANTS ARSEGS ALA-301; PRO-319; LEU-375; ARG-414 AND GLY-467;

Functional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in Dopa-responsive dystonia.
Fossbakk A.; Kleppe R.; Knappskog P.M.; Martinez A.; Haavik J.;
Hum. Mutat. 35:880-890(2014)
Cited for: CHARACTERIZATION OF VARIANTS ARSEGS TYR-207; GLY-227; HIS-233; PRO-236; THR-241; TYR-246; SER-247; GLY-259; PRO-276; ALA-301; SER-309; MET-314; PRO-319; TRP-328; HIS-337; PHE-359; LEU-375; VAL-376; MET-387; THR-394; MET-399; LYS-412; ARG-414; PRO-441; GLY-467; LEU-492; MET-494; GLY-498 AND GLN-510;

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.