TRHR

protein-coding

thyrotropin releasing hormone receptor, the group of Peptide receptors

Gene summary

This gene encodes a G protein-coupled receptor for thyrotropin-releasing hormone (TRH). Upon binding to TRH, this receptor activates the inositol phospholipid-calcium-protein kinase C transduction pathway. Mutations in this gene have been associated with generalized thyrotropin-releasing hormone resistance. [provided by RefSeq, Sep 2011]

MANE transcript

NM_003301.7

Inheritance

ClinVar variants

P:6U:44B:16

Top phenotype

Hypothyroidism, congenital, nongoitrous, 7

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr8:109,086,585-109,121,565

External References & Databases

Ensembl (ENSG00000174417)

Transcript & Mutation Effects

hg38 • Region Span ~35.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

resistance to thyrotropin-releasing hormone syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020503

Submitter: Orphanet

hypothyroidism, congenital, nongoitrous, 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032819

Submitter: Labcorp Genetics (formerly Invitae)

hypothyroidism, congenital, nongoitrous, 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032819

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypothyroidism, congenital, nongoitrous, 7AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Individuals may manifest with sequalae of hypothyroidism, and medical treatment (with thyroid hormone replacement) can be effective

Refs: 9141550; 19213692; 26735259; 28419241

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRHR variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 37

not providedTotal: 16

Hypothyroidism, congenital, nongoitrous, 7Total: 8

not specifiedTotal: 5

TRHR-related disorderTotal: 4

Congenital hypothyroidismTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003301.7. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar	5 clinvar	13
missense	1 clinvar	1 clinvar	44 clinvar	3 clinvar		49
nonsense	1 clinvar	1 clinvar				2
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)						0
Total	2	4	44	11	5	66

Highest pathogenic variant AF is 0.00025487138

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003301.7	RefSeq	NP_003292.1	2	MANE Select
ENST00000518632.2	Ensembl	ENSP00000430711.2	2	MANE Select
ENST00000311762.2	Ensembl	ENSP00000309818.2	2	Standard
ENST00000311762.3	Ensembl	ENSP00000309818.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Calcium signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Peptide GPCRs
GPCRs, Class A Rhodopsin-like
Signaling by GPCR

Biological Process

G protein-coupled receptor signaling pathway

Molecular Function

thyrotropin-releasing hormone receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000518632
Coding exons: 2
Length: 32964
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 69
Defined: 125744
p: 0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.944	163	201	0.813	0.00000954	2624
Missense (PolyPhen)		45	68.452	0.6574		922
Synonymous	0.147	75	76.6	0.979	0.00000387	788
Loss of Function	2.43	3	12.2	0.247	6.25e-7	156

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00023	0.00018	rare
European (Non-Finnish)	0.00051	0.00046	rare
South Asian	0.00026	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for thyrotropin-releasing hormone. This receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.;

Recessive Scores

pRec: 0.229

Intolerance Scores

LoFtool: 0.703
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.339

Gene Damage Prediction

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