TH

tyrosine hydroxylase

Basic information

Region (hg38): 11:2163929-2171815

Links

ENSG00000180176 ∙ NCBI:7054 ∙ OMIM:191290 ∙ HGNC:11782 ∙ Uniprot:P07101 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tyrosine hydroxylase deficiency (Definitive), mode of inheritance: AR
• TH-deficient dopa-responsive dystonia (Definitive), mode of inheritance: AR
• TH-deficient dopa-responsive dystonia (Strong), mode of inheritance: AR
• TH-deficient dopa-responsive dystonia (Supportive), mode of inheritance: AR
• tyrosine hydroxylase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Segawa syndrome, autosomal recessive	AR	Biochemical	The condition can have infantile onset, and treatment (eg, with L-dopa alone or combined with other medications), can be effective, though has not been reported to be universally so	Biochemical; Neurologic	7814018; 8817341; 9732974; 10407773; 10585338; 11196107; 16049992; 17696123; 10753262; 11246459; 11241071; 11134401; 11921123; 12891655; 14705130; 15505183; 18058633; 19282209; 20056467; 20301610; 21937992; 21940685; 22264700; 22691284; 22815559; 23389938

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TH gene.

• Autosomal recessive DOPA responsive dystonia (39 variants)
• not provided (2 variants)
• Dystonic disorder (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TH 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				293	7	300
missense	3	20	260	7		290
nonsense	15	15				30
start loss						0
frameshift	22	35	1			58
inframe indel		1	4			5
splice donor/acceptor (+/-2bp)		34	1			35
splice region		1	23	68	3	95
non coding		1	13	159	30	203
Total	40	106	279	459	37

Highest pathogenic variant AF is 0.000138

Variants in TH

This is a list of pathogenic ClinVar variants found in the TH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-2163956-C-T		Transient Neonatal Diabetes, Dominant/Recessive • Maturity onset diabetes mellitus in young • Autosomal recessive DOPA responsive dystonia • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Sep 21, 2020)
11-2164098-G-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jan 12, 2018)
11-2164124-C-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jan 13, 2018)
11-2164131-G-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jan 13, 2018)
11-2164179-G-A		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Apr 27, 2017)
11-2164181-G-A		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jan 13, 2018)
11-2164224-G-A		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jan 13, 2018)
11-2164224-G-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Apr 11, 2020)
11-2164225-C-G		Autosomal recessive DOPA responsive dystonia	Likely benign (Jun 02, 2020)
11-2164237-C-A		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Aug 16, 2022)
11-2164237-C-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Aug 22, 2022)
11-2164240-A-G			Uncertain significance (Feb 01, 2022)
11-2164248-C-T		Autosomal recessive DOPA responsive dystonia	Likely benign (Jul 01, 2022)
11-2164251-C-A		Autosomal recessive DOPA responsive dystonia	Likely benign (Nov 06, 2023)
11-2164251-C-T		Autosomal recessive DOPA responsive dystonia	Likely benign (Oct 24, 2023)
11-2164252-G-A		Autosomal recessive DOPA responsive dystonia • Inborn genetic diseases	Uncertain significance (Jan 10, 2023)
11-2164254-A-G		Autosomal recessive DOPA responsive dystonia	Likely benign (Mar 02, 2021)
11-2164257-G-C		Autosomal recessive DOPA responsive dystonia	Conflicting classifications of pathogenicity (Sep 12, 2023)
11-2164263-G-T		Autosomal recessive DOPA responsive dystonia	Likely benign (Sep 15, 2021)
11-2164265-T-C		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Mar 09, 2020)
11-2164266-G-A		Autosomal recessive DOPA responsive dystonia	Likely benign (Apr 22, 2019)
11-2164267-T-C		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Jun 27, 2022)
11-2164268-C-G		Autosomal recessive DOPA responsive dystonia	Uncertain significance (May 20, 2021)
11-2164269-C-T		Autosomal recessive DOPA responsive dystonia	Likely benign (Apr 07, 2023)
11-2164274-C-T		Autosomal recessive DOPA responsive dystonia	Uncertain significance (Aug 23, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TH	protein_coding	protein_coding	ENST00000381178	14	7949

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000169	0.993	125563	0	39	125602	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.564	321	351	0.915	0.0000246	3327
Missense in Polyphen		106	142.71	0.74276		1390
Synonymous	-0.191	160	157	1.02	0.0000117	1093
Loss of Function	2.42	14	27.8	0.504	0.00000146	298

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000269	0.000268
Ashkenazi Jewish	0.0000996	0.0000993
East Asian	0.000990	0.000979
Finnish	0.00	0.00
European (Non-Finnish)	0.0000925	0.0000881
Middle Eastern	0.000990	0.000979
South Asian	0.0000699	0.0000653
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays an important role in the physiology of adrenergic neurons.
• Disease: DISEASE: Note=May play a role in the pathogenesis of Parkinson disease (PD). A genome-wide copy number variation analysis has identified a 34 kilobase deletion over the TH gene in a PD patient but not in any controls. {ECO:0000269|PubMed:20809526}.
• Pathway: Folate biosynthesis - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Tyrosine metabolism - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics;Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction);Tyrosine hydroxylase deficiency;Catecholamine Biosynthesis;Aromatic L-Aminoacid Decarboxylase Deficiency;Nicotine Activity on Dopaminergic Neurons;Parkinsons Disease Pathway;Dopamine metabolism;Dopaminergic Neurogenesis;Amino Acid metabolism;Biogenic Amine Synthesis;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Monoamine Transport;Metabolism of amino acids and derivatives;Metabolism;ATF-2 transcription factor network;catecholamine biosynthesis;Catecholamine biosynthesis;Tyrosine metabolism;Amine-derived hormones;AP-1 transcription factor network;Alpha-synuclein signaling;p38 signaling mediated by MAPKAP kinases (Consensus)

Recessive Scores

• pRec: 0.855

Intolerance Scores

• loftool: 0.0190
• rvis_EVS: -0.95
• rvis_percentile_EVS: 9.27

Haploinsufficiency Scores

• pHI: 0.749
• hipred: Y
• hipred_score: 0.793
• ghis: 0.439

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Th
• Phenotype: normal phenotype; 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); 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); neoplasm; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system 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); vision/eye phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: th
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: response to hypoxia;synaptic transmission, dopaminergic;response to amphetamine;heart morphogenesis;dopamine biosynthetic process from tyrosine;fatty acid metabolic process;sphingolipid metabolic process;heart development;visual perception;sensory perception of sound;learning;memory;mating behavior;locomotory behavior;regulation of heart contraction;response to water deprivation;response to light stimulus;response to herbicide;response to salt stress;anatomical structure morphogenesis;animal organ morphogenesis;response to zinc ion;multicellular organism aging;response to activity;aminergic neurotransmitter loading into synaptic vesicle;glycoside metabolic process;phthalate metabolic process;cerebral cortex development;response to nutrient levels;response to estradiol;response to lipopolysaccharide;isoquinoline alkaloid metabolic process;social behavior;response to isolation stress;response to immobilization stress;neurotransmitter biosynthetic process;terpene metabolic process;dopamine biosynthetic process;epinephrine biosynthetic process;norepinephrine biosynthetic process;catecholamine biosynthetic process;eye photoreceptor cell development;circadian sleep/wake cycle;eating behavior;response to peptide hormone;pigmentation;response to ethanol;response to ether;response to pyrethroid;embryonic camera-type eye morphogenesis;response to corticosterone;response to electrical stimulus;phytoalexin metabolic process;oxidation-reduction process;cellular response to manganese ion;cellular response to alkaloid;cellular response to nicotine;cellular response to glucose stimulus;cellular response to growth factor stimulus
• Cellular component: nucleus;cytoplasm;mitochondrion;smooth endoplasmic reticulum;cytosol;synaptic vesicle;cytoplasmic side of plasma membrane;axon;dendrite;cytoplasmic vesicle;melanosome membrane;neuron projection;terminal bouton;perikaryon
• Molecular function: tyrosine 3-monooxygenase activity;protein binding;ferrous iron binding;ferric iron binding;amino acid binding;oxygen binding;enzyme binding;protein domain specific binding;tetrahydrobiopterin binding;dopamine binding