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UniProtKB/Swiss-Prot P04150: Variant p.Val423Ala

Glucocorticoid receptor
Gene: NR3C1
Variant information

Variant position:  423
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Unclassified
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 Valine (V) to Alanine (A) at position 423 (V423A, p.Val423Ala).
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 medium size and hydrophobic (V) to small size and hydrophobic (A)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
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; unknown pathological significance; reduces transactivation activity; delays nuclear translocation; does not exert a dominant negative effect; impairs DNA binding.
Any additional useful information about the variant.



Sequence information

Variant position:  423
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:   SSPPSSSSTATTGPPPKLCL  V CSDEASGCHYGVLTCGSCKV
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                         SSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKV

Mouse                         SSPPSSSSTAT-GPPPKLCLVCSDEASVCHYGVLTCGSCKV

Rat                           SSPPSSSSAAT-GPPPKLCLVCSDEASGCHYGVLTCGSCKV

Pig                           SSPPSSSSAAT-GPPPKLCLVCSDEASGCHYGVLTCGSCKV

Rabbit                        SSPPSNSTTAA-GPPPKLCLVCSDEASGCHYGVLTCGSCKV

Xenopus laevis                SPSPSTSSTST-GPPPKLCLVCSDEASGCHYGVLTCGSCKV

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
Zinc finger 421 – 441 NR C4-type
Modified residue 404 – 404 Phosphoserine; by GSK3-beta
Cross 419 – 419 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 404 – 404 S -> A. Abolishes phosphorylation. Does not affect translocation to the nucleus following ligand stimulation. Increases protein half-life and transcriptional repressor activity. Alters repertoire of regulated genes. Increases cell death.
Mutagenesis 404 – 404 S -> D. Does not affect translocation to the nucleus following ligand stimulation.
Turn 422 – 424


Literature citations

A novel point mutation in the DNA-binding domain (DBD) of the human glucocorticoid receptor causes primary generalized glucocorticoid resistance by disrupting the hydrophobic structure of its DBD.
Roberts M.L.; Kino T.; Nicolaides N.C.; Hurt D.E.; Katsantoni E.; Sertedaki A.; Komianou F.; Kassiou K.; Chrousos G.P.; Charmandari E.;
J. Clin. Endocrinol. Metab. 98:E790-E795(2013)
Cited for: CHARACTERIZATION OF VARIANT GCCR ALA-423;

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.