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UniProtKB/Swiss-Prot P03372: Variant p.Gln375His

Estrogen receptor
Gene: ESR1
Chromosomal location: 6q25.1
Variant information

Variant position:  375
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 Glutamine (Q) to Histidine (H) at position 375 (Q375H, p.Gln375His).
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:  Similar physico-chemical property. Both residues are medium size and polar.
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:  Estrogen resistance (ESTRR) [MIM:615363]: A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. {ECO:0000269|PubMed:23841731, ECO:0000269|PubMed:27754803}. 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 ESTRR; results in highly reduced activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  375
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  595
The length of the canonical sequence.

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.

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.

Chain 1 – 595 Estrogen receptor
Domain 311 – 547 NR LBD
Region 262 – 595 Interaction with AKAP13
Region 264 – 595 Self-association
Region 311 – 595 Transactivation AF-2
Mutagenesis 364 – 364 V -> E. Has higher transcriptional activity in the absence of wild type ER. Inhibits transcriptional activity when coexpressed with the wild type receptor.
Mutagenesis 386 – 386 I -> C. Loss of transmembrane localization, no effect on peripheral membrane localization. Impairs activation of estrogen-induced activation of NOS3 and production of nitric oxide. No effect on binding to ERES.
Helix 372 – 394

Literature citations

Delayed puberty and estrogen resistance in a woman with estrogen receptor alpha variant.
Quaynor S.D.; Stradtman E.W. Jr.; Kim H.G.; Shen Y.; Chorich L.P.; Schreihofer D.A.; Layman L.C.;
N. Engl. J. Med. 369:164-171(2013)

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.