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UniProtKB/Swiss-Prot Q9GZT9: Variant p.Asp4Glu

Egl nine homolog 1
Gene: EGLN1
Variant information

Variant position:  4
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LB/B
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Aspartate (D) to Glutamate (E) at position 4 (D4E, p.Asp4Glu).
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 acidic.
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

Polymorphism:  Variations in EGLN1 are associated with adaptation to high altitude (PubMed:20838600, PubMed:20466884, PubMed:24711448, PubMed:25129147). High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body and leads to an elevation of hematocrit levels and an increased number of erythrocytes (polycythemia) in non-adapted individuals. Genetic variations in EGLN1 contribute to adaptation to high altitute by maintaining hematocrit levels comparable to those for populations living at sea level and are present in two high-altitude regions where humans have lived for millennia, the Andean Altiplano and the Tibetan Plateau (PubMed:20838600, PubMed:20466884). Variants Glu-4 and Ser-127, which are frequently associated together and are present in the majority of Tibetan populations, participate in adaptation to high altitude (PubMed:24711448, PubMed:25129147). Molecular mechanisms explaining this adaptation are however unclear. According to a report, variants Glu-4 and Ser-127 lead to decreased interaction with PTGES3 and subsequent decrease of HIF alpha proteins degradation (PubMed:24711448). According to a second report, Glu-4 and Ser-127 haplotype enhances the catalytic activity under hypoxic conditions, promoting increased HIF alpha proteins degradation, thereby abrogating hypoxia-induced and HIF alpha-mediated augmentation of erythropoiesis and protecting Tibetans from polycythemia at high altitude (PubMed:25129147).
Additional information on the polymorphism described.

Variant description:  Increased protection from polycythemia at high altitude; when associated with S-127.
Any additional useful information about the variant.

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

Sequence information

Variant position:  4
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  426
The length of the canonical sequence.

Location on the sequence:   MAN  D SGGPGGPSPSERDRQYCELC
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                         MANDSGGPGGPSPSERDRQYCELC

Mouse                         MASDSGGPGVLSASERDRQYCELC

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.

Initiator methionine 1 – 1 Removed
Chain 2 – 426 Egl nine homolog 1
Metal binding 21 – 21 Zinc 1
Metal binding 24 – 24 Zinc 1
Modified residue 2 – 2 N-acetylalanine
Modified residue 12 – 12 Phosphoserine

Literature citations

Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing.
Song D.; Li L.S.; Arsenault P.R.; Tan Q.; Bigham A.W.; Heaton-Johnson K.J.; Master S.R.; Lee F.S.;
J. Biol. Chem. 289:14656-14665(2014)

A genetic mechanism for Tibetan high-altitude adaptation.
Lorenzo F.R.; Huff C.; Myllymaeki M.; Olenchock B.; Swierczek S.; Tashi T.; Gordeuk V.; Wuren T.; Ri-Li G.; McClain D.A.; Khan T.M.; Koul P.A.; Guchhait P.; Salama M.E.; Xing J.; Semenza G.L.; Liberzon E.; Wilson A.; Simonson T.S.; Jorde L.B.; Kaelin W.G. Jr.; Koivunen P.; Prchal J.T.;
Nat. Genet. 46:951-956(2014)

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.