GeneBe

TSHR

protein-coding

thyroid stimulating hormone receptor, the group of Glycoprotein hormone receptors

Gene summary

The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

MANE transcript

NM_000369.5

Inheritance

AD, AR

ClinVar variants

P:124U:147B:205

Top phenotype

Hyperthyroidism, familial, gestational; Hyperthyroidism, nonautoimmune; Hypothyroidism, congenital, nongoitrous, 1

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr14:80,954,989-81,146,306

External References & Databases

Ensembl (ENSG00000165409)NCBI Gene (7253)OMIM (603372)HGNC:12373GenCCUniProt (P16473)AlphaFoldClinVar (TSHR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~191.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial hyperthyroidism due to mutations in TSH receptorSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012203

Submitter: Orphanet

athyreosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019855

Submitter: Orphanet

familial gestational hyperthyroidismDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011309

Submitter: G2P

hypothyroidism due to TSH receptor mutationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010142

Submitter: PanelApp Australia

hypothyroidism due to TSH receptor mutationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010142

Submitter: Labcorp Genetics (formerly Invitae)

familial gestational hyperthyroidismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011309

Submitter: PanelApp Australia

thyroid hypoplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019861

Submitter: Orphanet

familial gestational hyperthyroidismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011309

Submitter: Orphanet

hypothyroidism due to TSH receptor mutationsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010142

Submitter: Orphanet

hypothyroidism due to TSH receptor mutationsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010142

Submitter: G2P

familial hyperthyroidism due to mutations in TSH receptorSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012203

Submitter: PanelApp Australia

familial hyperthyroidism due to mutations in TSH receptorSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012203

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperthyroidism, familial, gestational; Hyperthyroidism, nonautoimmune; Hypothyroidism, congenital, nongoitrous, 1AD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: In Hyperthyroidism, familial, gestational, recognition and treatment of hyperthyroidism during pregnancy (eg, with propylthiouracil) can lead to positive gestational outcomes; In Hyperthyroidism (including in early-onset types), recognition can allow prompt treatment with medical or surgical ablation, as recurrent hyperthyroidism after subtotal thyroidectomy (necessitating repeat treatment), has been described; In conditions resulting in hypothyroidism, medical treatment of hypothyroidism (with T4) can be effective

Comments: Variants may also be associated with a number of thyroid-related presentations

Refs: 7920658; 7800007; 7528344; 8954020; 9185526; 9329388; 9100579; 9385128; 9854118; 10487707; 12050212; 20146656; 20718767; 21186955; 21283701; 21677043; 21714469; 22405933; 22763653; 22876533; 23154162; 23329763; 23412867; 23563316; 23698639Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TSHR variants in ClinVar

21 Conditions Cataloged
not providedTotal: 409
Hypothyroidism due to TSH receptor mutationsTotal: 104
Familial hyperthyroidism due to mutations in TSH receptorTotal: 84
Inborn genetic diseasesTotal: 70
not specifiedTotal: 63
TSHR-related disorderTotal: 46
Familial gestational hyperthyroidismTotal: 33
Ovarian cancerTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000369.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
182
clinvar
3
clinvar
 188
missense
19
clinvar
47
clinvar
142
clinvar
17
clinvar
3
clinvar
 228
nonsense
14
clinvar
6
clinvar
 20
start loss
1
clinvar
 1
frameshift
12
clinvar
16
clinvar
1
clinvar
 29
splice donor/acceptor (+/-2bp)
9
clinvar
1
clinvar
 10
Total45791471996476

Highest pathogenic variant AF is 0.00035921056

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000369.5RefSeqNP_000360.210MANE Select
ENST00000298171.7EnsemblENSP00000298171.210MANE Select
NM_001018036.3RefSeqNP_001018046.19Standard
NM_001142626.3RefSeqNP_001136098.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tshrDanio rerio

Structure: xanthophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Regulation of lipolysis in adipocytes - Homo sapiens (human)
  • Thyroid hormone synthesis - Homo sapiens (human)
  • Autoimmune thyroid disease - Homo sapiens (human)
  • cAMP signaling pathway - Homo sapiens (human)
  • Neuroactive ligand-receptor interaction - Homo sapiens (human)

Biological Process

  • cell surface receptor signaling pathway
  • G protein-coupled receptor signaling pathway
  • G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
  • adenylate cyclase-activating G protein-coupled receptor signaling pathway
  • activation of adenylate cyclase activity

Molecular Function

  • thyroid-stimulating hormone receptor activity
  • protein binding
  • G protein-coupled peptide receptor activity
  • signaling receptor activity
  • protein-containing complex binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • cell surface
  • basolateral plasma membrane
  • receptor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000541158
Coding exons
10
Length
191314
Individuals with no LoFs
125656
Homozygous LoFs
0
Heterozygous LoFs
92
Defined
125748
p
0.000366
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.3343894080.9530.00002315060
Missense (PolyPhen)146169.460.861542132
Synonymous-0.7281761641.070.00001011471
Loss of Function0.5042426.80.8950.00000125359

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000350.00035rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000590.00059rare
South Asian0.0000980.000098rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin (PubMed:11847099, PubMed:12045258). Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin (PubMed:12045258). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11847099). Plays a central role in controlling thyroid cell metabolism (By similarity). {ECO:0000250|UniProtKB:P21463, ECO:0000269|PubMed:11847099, ECO:0000269|PubMed:12045258}.;
Disease
DISEASE: Note=Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH- independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers).; DISEASE: Note=Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation.; DISEASE: Hypothyroidism, congenital, non-goitrous, 1 (CHNG1) [MIM:275200]: A non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. It presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland. {ECO:0000269|PubMed:10720030, ECO:0000269|PubMed:11095460, ECO:0000269|PubMed:11442002, ECO:0000269|PubMed:12050212, ECO:0000269|PubMed:14725684, ECO:0000269|PubMed:15531543, ECO:0000269|PubMed:25978107, ECO:0000269|PubMed:7528344, ECO:0000269|PubMed:8954020, ECO:0000269|PubMed:9100579, ECO:0000269|PubMed:9185526, ECO:0000269|PubMed:9329388}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial gestational hyperthyroidism (HTFG) [MIM:603373]: A condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy. {ECO:0000269|PubMed:9854118}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperthyroidism, non-autoimmune (HTNA) [MIM:609152]: A condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. Typical features of Graves disease such as exophthalmia, myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of the thyroid gland are absent. {ECO:0000269|PubMed:10199795, ECO:0000269|PubMed:10852462, ECO:0000269|PubMed:11081252, ECO:0000269|PubMed:11127522, ECO:0000269|PubMed:11201847, ECO:0000269|PubMed:11517004, ECO:0000269|PubMed:11549687, ECO:0000269|PubMed:15163335, ECO:0000269|PubMed:7800007, ECO:0000269|PubMed:7920658, ECO:0000269|PubMed:8636266, ECO:0000269|PubMed:8964822, ECO:0000269|PubMed:9349581, ECO:0000269|PubMed:9360555, ECO:0000269|PubMed:9398746, ECO:0000269|PubMed:9589634}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.357

Intolerance Scores

LoFtool
0.272
RVIS EVS
0.01
RVIS percentile EVS
54.1

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.322

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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