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UniProtKB/Swiss-Prot P04150: Variant p.Tyr478Cys

Glucocorticoid receptor
Gene: NR3C1
Variant information

Variant position:  478
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Tyrosine (Y) to Cysteine (C) at position 478 (Y478C, p.Tyr478Cys).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and aromatic (Y) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In GCCR; decreased DNA-binding and transactivation activity; incomplete dexamethasone-induced translocation to the nucleus; no effect on dexamethasone-binding affinity compared with wild-type.
Any additional useful information about the variant.



Sequence information

Variant position:  478
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  777
The length of the canonical sequence.

Location on the sequence:   AGRNDCIIDKIRRKNCPACR  Y RKCLQAGMNLEARKTKKKIK
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Mouse                         AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Rat                           AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Pig                           AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Rabbit                        AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Xenopus laevis                AGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIK

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 777 Glucocorticoid receptor
DNA binding 418 – 493 Nuclear receptor
Modified residue 480 – 480 N6-acetyllysine
Modified residue 492 – 492 N6-acetyllysine
Modified residue 494 – 494 N6-acetyllysine
Modified residue 495 – 495 N6-acetyllysine
Mutagenesis 480 – 480 K -> A. Decrease in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer. Complete loss in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-492; A-494 and A-495.
Mutagenesis 492 – 492 K -> A. Decrease in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer. Complete loss in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-480; A-494 and A-495.
Mutagenesis 494 – 494 K -> A. Decrease in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-495. Complete loss in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-480; A-492 and A-495.
Mutagenesis 495 – 495 K -> A. Decrease in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-494. Complete loss in acetylation and in repression of its transcriptional activity by CLOCK-ARNTL/BMAL1 heterodimer; when associated with A-480; A-492 and A-494.
Helix 474 – 484


Literature citations

Three novel heterozygous point mutations of NR3C1 causing glucocorticoid resistance.
Vitellius G.; Fagart J.; Delemer B.; Amazit L.; Ramos N.; Bouligand J.; Le Billan F.; Castinetti F.; Guiochon-Mantel A.; Trabado S.; Lombes M.;
Hum. Mutat. 37:794-803(2016)
Cited for: VARIANTS GCCR SER-477; CYS-478 AND PRO-672; CHARACTERIZATION OF VARIANTS GCCR SER-477; CYS-478 AND CYS-478; FUNCTION; SUBCELLULAR LOCATION;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.