TSHR

thyroid stimulating hormone receptor, the group of Glycoprotein hormone receptors

Basic information

Region (hg38): 14:80954988-81146306

Links

ENSG00000165409 ∙ NCBI:7253 ∙ OMIM:603372 ∙ HGNC:12373 ∙ Uniprot:P16473 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypothyroidism due to TSH receptor mutations (Definitive), mode of inheritance: AR
• familial gestational hyperthyroidism (Definitive), mode of inheritance: AD
• familial hyperthyroidism due to mutations in TSH receptor (Supportive), mode of inheritance: AD
• hypothyroidism due to TSH receptor mutations (Supportive), mode of inheritance: AD
• athyreosis (Supportive), mode of inheritance: AD
• thyroid hypoplasia (Supportive), mode of inheritance: AD
• familial gestational hyperthyroidism (Supportive), mode of inheritance: AD
• familial hyperthyroidism due to mutations in TSH receptor (Strong), mode of inheritance: AD
• hypothyroidism due to TSH receptor mutations (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperthyroidism, familial, gestational; Hyperthyroidism, nonautoimmune; Hypothyroidism, congenital, nongoitrous, 1	AD/AR	Endocrine	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	Endocrine	7920658; 7800007; 7528344; 8954020; 9185526; 9329388; 9100579; 9385128; 9854118; 10487707; 12050212; 20146656; 20718767; 21186955; 21283701; 21677043; 21714469; 22405933; 22763653; 22876533; 23154162; 23329763; 23412867; 23563316; 23698639
Variants may also be associated with a number of thyroid-related presentations

ClinVar

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

• not provided (159 variants)
• Hypothyroidism due to TSH receptor mutations (106 variants)
• Familial hyperthyroidism due to mutations in TSH receptor (101 variants)
• not specified (34 variants)
• Inborn genetic diseases (22 variants)
• Familial gestational hyperthyroidism (10 variants)
• Ovarian cancer (10 variants)
• TSHR-related condition (5 variants)
• Congenital hypothyroidism (4 variants)
• Familial gestational hyperthyroidism;Familial hyperthyroidism due to mutations in TSH receptor;Hypothyroidism due to TSH receptor mutations (2 variants)
• TSHR-Related Disorders (2 variants)
• Familial hyperthyroidism due to mutations in TSH receptor;Hypothyroidism due to TSH receptor mutations;Familial gestational hyperthyroidism (2 variants)
• Bladder exstrophy-epispadias-cloacal extrophy complex (1 variants)
• Hypothyroidism (1 variants)
• Hereditary breast ovarian cancer syndrome (1 variants)
• Malignant tumor of breast (1 variants)
• THYROTROPIN RECEPTOR POLYMORPHISM (1 variants)
• Developmental delay;autistic features;Epilepsy (1 variants)
• Hypothyroidism due to TSH receptor mutations;Familial hyperthyroidism due to mutations in TSH receptor;Familial gestational hyperthyroidism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TSHR 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			4	49	5	58
missense	4	19	45	6	5	79
nonsense	5		1			6
start loss						0
frameshift	4	6	1			11
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region		1	3	6		10
non coding			19	22	19	60
Total	13	27	71	77	29

Highest pathogenic variant AF is 0.0000197

Variants in TSHR

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

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

Position	Type	Phenotype	Significance	ClinVar
14-80955515-C-T		Familial hyperthyroidism due to mutations in TSH receptor • Hypothyroidism due to TSH receptor mutations	Uncertain significance (Jan 12, 2018)
14-80955579-C-T		Familial hyperthyroidism due to mutations in TSH receptor • Hypothyroidism due to TSH receptor mutations	Uncertain significance (Jan 13, 2018)
14-80955621-G-A		Hypothyroidism due to TSH receptor mutations • Familial hyperthyroidism due to mutations in TSH receptor	Conflicting classifications of pathogenicity (Jan 13, 2018)
14-80955675-T-A		TSHR-related disorder	Likely benign (Oct 16, 2023)
14-80955699-C-CTGCA		TSHR-related disorder	Uncertain significance (Dec 25, 2018)
14-80955702-C-T			Pathogenic (Oct 20, 2023)
14-80955731-G-A			Likely benign (Dec 22, 2023)
14-80955735-C-T			Likely benign (Aug 11, 2023)
14-80955740-C-T			Likely benign (Sep 04, 2023)
14-80955743-A-G			Likely benign (Sep 05, 2023)
14-80955745-TG-T			Pathogenic (Nov 17, 2023)
14-80955767-C-A			Pathogenic (Nov 10, 2023)
14-80955767-C-G		Inborn genetic diseases	Uncertain significance (Jun 05, 2023)
14-80955770-G-A			Likely benign (Dec 21, 2023)
14-80955773-C-T			Likely benign (May 22, 2023)
14-80955780-G-A		Hypothyroidism due to TSH receptor mutations • Familial hyperthyroidism due to mutations in TSH receptor • not specified • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 04, 2023)
14-80955786-G-C		THYROTROPIN RECEPTOR POLYMORPHISM • not specified • Familial hyperthyroidism due to mutations in TSH receptor • Hypothyroidism due to TSH receptor mutations	Benign/Likely benign (Jan 31, 2024)
14-80955800-C-A			Likely benign (Oct 14, 2023)
14-80955802-G-C		Hypothyroidism due to TSH receptor mutations • Developmental delay;autistic features;Epilepsy • Familial hyperthyroidism due to mutations in TSH receptor	Pathogenic (Jan 01, 2016)
14-80955814-A-G		Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
14-80955824-C-T			Likely benign (Nov 10, 2023)
14-80955825-A-G		not specified	Likely benign (Jan 16, 2024)
14-80955828-T-C			Likely benign (Sep 14, 2023)
14-80955833-G-T			Likely benign (Feb 05, 2023)
14-80955834-C-A		not specified • Hypothyroidism due to TSH receptor mutations • Familial hyperthyroidism due to mutations in TSH receptor • Familial gestational hyperthyroidism	Benign (Feb 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TSHR	protein_coding	protein_coding	ENST00000541158	10	191314

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.04e-15	0.0370	125656	0	92	125748	0.000366

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.334	389	408	0.953	0.0000231	5060
Missense in Polyphen		146	169.46	0.86154		2132
Synonymous	-0.728	176	164	1.07	0.0000101	1471
Loss of Function	0.504	24	26.8	0.895	0.00000125	359

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000655	0.000655
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000590	0.000589
Middle Eastern	0.000109	0.000109
South Asian	0.0000980	0.0000980
Other	0.000326	0.000326

dbNSFP

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.
• Pathway: 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);Thyroxine (Thyroid Hormone) Production;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Peptide GPCRs;Signaling by GPCR;Signal Transduction;G alpha (s) signalling events;Hormone ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;Arf6 trafficking events;TSH;GPCR downstream signalling;Arf6 signaling events (Consensus)

Recessive Scores

• pRec: 0.357

Intolerance Scores

• loftool: 0.272
• rvis_EVS: 0.01
• rvis_percentile_EVS: 54.1

Haploinsufficiency Scores

• pHI: 0.196
• hipred: Y
• hipred_score: 0.551
• ghis: 0.479

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.322

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tshr
• Phenotype: immune system phenotype; skeleton 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); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; vision/eye phenotype; reproductive system 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); hematopoietic system phenotype; neoplasm; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: tshr
• Affected structure: xanthophore
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• 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;cell-cell signaling;positive regulation of cell population proliferation;hormone-mediated signaling pathway;thyroid-stimulating hormone signaling pathway;positive regulation of adenylate cyclase activity;positive regulation of cold-induced thermogenesis;cellular response to glycoprotein;cellular response to thyrotropin-releasing hormone
• Cellular component: plasma membrane;integral component of plasma membrane;cell surface;basolateral plasma membrane;receptor complex
• Molecular function: thyroid-stimulating hormone receptor activity;protein binding;G protein-coupled peptide receptor activity;signaling receptor activity;protein-containing complex binding