GeneBe

NR3C1

protein-coding

nuclear receptor subfamily 3 group C member 1, the group of Nuclear receptor subfamily 3 group C

Gene summary

This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

Previous symbols:
  • GRL

MANE transcript

NM_000176.3

Inheritance

AD, AR

ClinVar variants

P:19U:166B:41

Top phenotype

Glucocorticoid resistance

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr5:143,277,931-143,435,512

External References & Databases

Ensembl (ENSG00000113580)NCBI Gene (2908)OMIM (138040)HGNC:7978GenCCUniProt (P04150)AlphaFoldClinVar (NR3C1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~157.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glucocorticoid resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014421

Submitter: PanelApp Australia

glucocorticoid resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014421

Submitter: Labcorp Genetics (formerly Invitae)

glucocorticoid resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014421

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

glucocorticoid resistanceSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014421

Submitter: Orphanet

glucocorticoid resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014421

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glucocorticoid resistanceAD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Treatment focuses on suppression of excess ACTH production, and may include high-dose mineralocorticoid-sparing synthetic glucocorticoids; Individuals may also display other endocrinologic anomalies (eg, growth hormone deficiency), and surveillance and prompt recognition and treatment may be beneficial

Refs: 186477; 6841559; 2996089; 1704018; 8445027; 8863343; 11701741; 11589680; 11932321; 12050230; 12754700; 14764810; 15769988; 16449337; 17635946; 18319312; 19694013; 19933394; 23076843Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR3C1 variants in ClinVar

10 Conditions Cataloged
Glucocorticoid resistanceTotal: 104
not providedTotal: 86
Inborn genetic diseasesTotal: 68
not specifiedTotal: 4
NR3C1-related disorderTotal: 4
GLUCOCORTICOID RESISTANCE, CELLULARTotal: 1
Prostate cancerTotal: 1
GLUCOCORTICOID RESISTANCE, MILDTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000176.3. 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
8
clinvar
26
clinvar
5
clinvar
 39
missense
7
clinvar
4
clinvar
153
clinvar
9
clinvar
1
clinvar
 174
nonsense
2
clinvar
1
clinvar
 3
start loss
0
frameshift
2
clinvar
1
clinvar
2
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
2
clinvar
 5
Total127166356226

Highest pathogenic variant AF is 0.0000013685957

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000176.3RefSeqNP_000167.18MANE Select
ENST00000394464.7EnsemblENSP00000377977.28MANE Select
NM_001018074.1RefSeqNP_001018084.18Standard
NM_001018075.1RefSeqNP_001018085.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
nr3c1Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • Glucocorticoid Pathway (Peripheral Tissue), Pharmacodynamics
  • Prednisolone Metabolism Pathway
  • Prednisolone Action Pathway
  • NHR

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • chromatin organization
  • transcription, DNA-templated
  • regulation of transcription, DNA-templated
  • transcription by RNA polymerase II

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • core promoter binding
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA-binding transcription factor activity

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm
  • mitochondrial matrix
  • microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000231509
Coding exons
8
Length
157582
Individuals with no LoFs
125740
Homozygous LoFs
0
Heterozygous LoFs
8
Defined
125748
p
0.0000318
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.842933960.7400.00001985073
Missense (PolyPhen)63153.410.410662015
Synonymous-0.1721531501.020.000008091525
Loss of Function4.50532.90.1520.00000176416

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000350.000035rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor for glucocorticoids (GC) (PubMed:27120390). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity). {ECO:0000250|UniProtKB:P06537, ECO:0000269|PubMed:25775514, ECO:0000269|PubMed:27120390, ECO:0000269|PubMed:9590696}.; FUNCTION: Isoform Beta: Acts as a dominant negative inhibitor of isoform Alpha (PubMed:7769088, PubMed:8621628, PubMed:20484466). Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253). Loses this transcription modulator function on its own (PubMed:20484466). Has no hormone-binding activity (PubMed:8621628). May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253). Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253). {ECO:0000250|UniProtKB:P06537, ECO:0000269|PubMed:19248771, ECO:0000269|PubMed:20484466, ECO:0000269|PubMed:26711253, ECO:0000269|PubMed:7769088, ECO:0000269|PubMed:8621628}.; FUNCTION: Isoform GR-P: Increases activity of isoform Alpha. {ECO:0000269|PubMed:11358809}.; FUNCTION: Isoform 10: Has transcriptional activation activity. {ECO:0000269|PubMed:20484466}.; FUNCTION: Isoform Alpha-C2: Has transcriptional activation activity. {ECO:0000269|PubMed:15866175}.; FUNCTION: Isoform Alpha-D1: Has transcriptional activation activity. {ECO:0000269|PubMed:15866175}.; FUNCTION: Isoform Alpha-D3: Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). {ECO:0000269|PubMed:15866175, ECO:0000269|PubMed:23303127, ECO:0000269|PubMed:23820903}.;
Disease
DISEASE: Glucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:11701741, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:1704018, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:20335448, ECO:0000269|PubMed:21362280, ECO:0000269|PubMed:23426617, ECO:0000269|PubMed:24483153, ECO:0000269|PubMed:26031419, ECO:0000269|PubMed:26541474, ECO:0000269|PubMed:27120390, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.930

Intolerance Scores

LoFtool
0.0657
RVIS EVS
-0.16
RVIS percentile EVS
42.16

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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