NR3C1

Chr 5

nuclear receptor subfamily 3 group C member 1

Also known as: GCCR, GCR, GCRST, GR, GRL

NCBI Gene: 2908 ENSG00000113580 UniProt: P04150

The glucocorticoid receptor functions as a transcription factor that binds to glucocorticoid response elements to regulate gene expression and modulates other transcription factors, affecting inflammatory responses, cellular proliferation, and differentiation. Mutations cause glucocorticoid resistance with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.32

Clinical Summary— NR3C1

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 233 VUS of 332 total submissions

💊

Clinical Trials

11 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.970

Z-score 4.50

OE 0.15 (0.08–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.84Z-score

OE missense 0.74 (0.67–0.81)

293 obs / 396.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.32)

0≤0.351.4

Missense OE?0.74 (0.67–0.81)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 5 / 32.9Missense obs/exp: 293 / 396.1Syn Z: -0.17

This gene — mechanism propensity

0.3892th %ile

GOF

0.3491th %ile

LOF

0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 41% of P/LP variants are LoF · LOEUF 0.32

DN1 literature citation

Literature Evidence

DNGlucocorticoid receptor-beta and receptor-gamma exert dominant negative effect on gene repression but not on gene induction.1

LOFHaploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

332 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic5

VUS233

Likely Benign50

Benign11

Conflicting6

Pathogenic

Likely Pathogenic

233

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	7	1	0	12
Likely Pathogenic	3	2	0	0	5
VUS	3	150	74	6	233
Likely Benign	0	7	17	26	50
Benign	0	1	4	6	11
Conflicting	—				6
Total	10	167	96	38	317

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap NR3C1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →