GeneBe

THRB

protein-coding

thyroid hormone receptor beta, the group of Thyroid hormone receptors

Gene summary

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • ERBA2
  • PRTH

MANE transcript

NM_001354712.2

Inheritance

AR, AD, SD

ClinVar variants

P:95U:109B:30

Top phenotype

Thyroid hormone resistance, generalized, autosomal dominant; Thyroid hormone resistance, selective pituitary; Thyroid hormone resistance, generalized, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr3:24,117,153-24,495,756

External References & Databases

Ensembl (ENSG00000151090)NCBI Gene (7068)OMIM (190160)HGNC:11799GenCCUniProt (P10828)AlphaFoldClinVar (THRB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~378.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

resistance to thyroid hormone due to a mutation in thyroid hormone receptor betaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0034217

Submitter: Orphanet

thyroid hormone resistance, generalized, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010131

Submitter: Labcorp Genetics (formerly Invitae)

thyroid hormone resistance, generalized, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008569

Submitter: Labcorp Genetics (formerly Invitae)

thyroid hormone resistance, generalized, autosomal dominantSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0008569

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Thyroid hormone resistance, generalized, autosomal dominant; Thyroid hormone resistance, selective pituitary; Thyroid hormone resistance, generalized, autosomal recessiveAD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: In Thyroid hormone resistance, generalized, unhelpful, potentially invasive treatment regimens that may involve adverse effects may be avoided with efficient (genetic) diagnosis, and medical treatment (eg, with types of triiodothyroacetic acid) may be beneficial related to biological parameters as well as sequelae affecting multiple systems, such as the cardiovascular and neurologic systems; In Thyroid hormone resistance, selective pituitary, affected individuals may more frequently benefit from efforts to lower serum thyroid hormone concentration

Refs: 4163616; 1159077; 6792914; 6287848; 3571851; 2510172; 2153155; 1991834; 1653889; 8381821; 8450877; 1400869; 8384535; 8496318; 8040303; 15913586; 17596672; 19268523; 19378427; 20020587; 22319036; 22696245; 22947347; 23134553; 23633200Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THRB variants in ClinVar

15 Conditions Cataloged
not providedTotal: 116
Thyroid hormone resistance, generalized, autosomal dominantTotal: 90
not specifiedTotal: 52
THRB-related disorderTotal: 48
Inborn genetic diseasesTotal: 30
HyperthyroidismTotal: 16
Selective pituitary resistance to thyroid hormoneTotal: 12
Thyroid hormone resistance, generalized, autosomal recessiveTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001354712.2. 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
5
clinvar
20
clinvar
2
clinvar
 27
missense
36
clinvar
47
clinvar
98
clinvar
8
clinvar
 189
nonsense
3
clinvar
1
clinvar
1
clinvar
 5
start loss
1
clinvar
 1
frameshift
5
clinvar
1
clinvar
 6
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
4
clinvar
 6
Total4550109282234

Highest pathogenic variant AF is 0.00000657964

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 153 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001354712.2RefSeqNP_001341641.18MANE Select
ENST00000646209.2EnsemblENSP00000496686.28MANE Select
NM_000461.5RefSeqNP_000452.28Standard
NM_001128176.3RefSeqNP_001121648.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
thrbDanio rerio

Structure: horizontal cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Thyroid hormone signaling pathway - Homo sapiens (human)
  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • NHR
  • Nuclear Receptors
  • Angiopoietin Like Protein 8 Regulatory Pathway

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • thyroid hormone mediated signaling pathway
  • transcription, DNA-templated
  • transcription initiation from RNA polymerase II promoter
  • multicellular organism development

Molecular Function

  • transcription regulatory region sequence-specific DNA binding
  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm
  • nuclear body
  • RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000396671
Coding exons
8
Length
378123
Individuals with no LoFs
125725
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125729
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.571452620.5540.00001613069
Missense (PolyPhen)1887.6390.20539971
Synonymous-1.4211899.91.180.00000653851
Loss of Function4.07121.30.04700.00000119261

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:16781732, ECO:0000269|PubMed:17418816, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:18798561, ECO:0000269|PubMed:19926848}.;
Disease
DISEASE: Generalized thyroid hormone resistance (GTHR) [MIM:188570]: A disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). {ECO:0000269|PubMed:10660344, ECO:0000269|PubMed:12511610, ECO:0000269|PubMed:12554782, ECO:0000269|PubMed:1314846, ECO:0000269|PubMed:1324420, ECO:0000269|PubMed:1563081, ECO:0000269|PubMed:1587388, ECO:0000269|PubMed:1619012, ECO:0000269|PubMed:1661299, ECO:0000269|PubMed:16804041, ECO:0000269|PubMed:1846005, ECO:0000269|PubMed:19268523, ECO:0000269|PubMed:2153155, ECO:0000269|PubMed:2510172, ECO:0000269|PubMed:7833659, ECO:0000269|PubMed:8175986, ECO:0000269|PubMed:8514853, ECO:0000269|PubMed:8664910, ECO:0000269|PubMed:8889584}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]: An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. {ECO:0000269|PubMed:1653889}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]: Variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. {ECO:0000269|PubMed:7528740, ECO:0000269|PubMed:8381821}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.511

Intolerance Scores

LoFtool
0.00875
RVIS EVS
-0.47
RVIS percentile EVS
23.04

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.896

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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