UniProtKB/Swiss-Prot P11362: Variant p.Trp666Arg

Fibroblast growth factor receptor 1
Gene: FGFR1
Chromosomal location: 8p11.1-p11.2
Variant information

Variant position:  666
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Tryptophan (W) to Arginine (R) at position 666 (W666R, p.Trp666Arg).
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 (W) to large size and basic (R)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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:  Hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:147950]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH-associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, KAL1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382).
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 HH2; with cleft palate.
Any additional useful information about the variant.



Sequence information

Variant position:  666
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  822
The length of the canonical sequence.

Location on the sequence:   RDIHHIDYYKKTTNGRLPVK  W MAPEALFDRIYTHQSDVWSF
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.

TypePositionsDescription
Chain 22 – 822 Fibroblast growth factor receptor 1
Topological domain 398 – 822 Cytoplasmic
Domain 478 – 767 Protein kinase
Modified residue 653 – 653 Phosphotyrosine; by autocatalysis
Modified residue 654 – 654 Phosphotyrosine; by autocatalysis
Alternative sequence 62 – 822 Missing. In isoform 3.
Alternative sequence 151 – 822 Missing. In isoform 16.
Alternative sequence 392 – 822 Missing. In isoform 17 and isoform 18.
Alternative sequence 663 – 822 Missing. In isoform 2, isoform 5, isoform 7, isoform 9, isoform 11 and isoform 13.
Mutagenesis 653 – 653 Y -> F. No effect on kinase activity. Loss of autophosphorylation and kinase activity; when associated with F-654.
Mutagenesis 654 – 654 Y -> F. Reduced kinase activity. Loss of autophosphorylation and kinase activity; when associated with F-653.
Helix 663 – 666


Literature citations

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.
Dode C.; Levilliers J.; Dupont J.-M.; De Paepe A.; Le Du N.; Soussi-Yanicostas N.; Coimbra R.S.; Delmaghani S.; Compain-Nouaille S.; Baverel F.; Pecheux C.; Le Tessier D.; Cruaud C.; Delpech M.; Speleman F.; Vermeulen S.; Amalfitano A.; Bachelot Y.; Bouchard P.; Cabrol S.; Carel J.-C.; Delemarre-van de Waal H.; Goulet-Salmon B.; Kottler M.-L.; Richard O.; Sanchez-Franco F.; Saura R.; Young J.; Petit C.; Hardelin J.-P.;
Nat. Genet. 33:463-465(2003)
Cited for: VARIANTS HH2 ASP-97; CYS-99; SER-167; TYR-277; MET-607; ARG-666; ARG-719 AND SER-772;

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.