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UniProtKB/Swiss-Prot P22607: Variant p.Lys650Glu

Fibroblast growth factor receptor 3
Gene: FGFR3
Chromosomal location: 4p16.3
Variant information

Variant position:  650
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 Lysine (K) to Glutamate (E) at position 650 (K650E, p.Lys650Glu).
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 basic (K) to medium size and acidic (E)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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:  Thanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8754806}. 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.

Involvement in disease:  Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:10471491, ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3.
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.

Involvement in disease:  Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. 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.

Involvement in disease:  Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis.
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 KERSEB, TD2, TGCT and BLC; bladder transitional cell carcinoma; somatic mutation; constitutively activated kinase with impaired internalization and degradation, resulting in prolonged FGFR3 signaling.
Any additional useful information about the variant.

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



Sequence information

Variant position:  650
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  806
The length of the canonical sequence.

Location on the sequence:   VMKIADFGLARDVHNLDYYK  K TTNGRLPVKWMAPEALFDRV
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                         VMKIADFGLARDVHNLDYYKKTTNGRLPVKWMAPEALFDRV

Mouse                         VMKIADFGLARDVHNLDYYKKTTNGRLPVKWMAPEALFDRV

Chicken                       VMKIADFGLARDVHNIDYYKKTTNGRLPVKWMAPEALFDRV

Xenopus laevis                VMKIADFGLARDIHNIDYYKKTTNGRLPVKWMAPEALFDRI

Zebrafish                     VMKIADFGLARDVHNIDYYKKTTNGRLPVKWMAPEALFDRV

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 23 – 806 Fibroblast growth factor receptor 3
Topological domain 397 – 806 Cytoplasmic
Domain 472 – 761 Protein kinase
Modified residue 647 – 647 Phosphotyrosine; by autocatalysis
Modified residue 648 – 648 Phosphotyrosine; by autocatalysis
Mutagenesis 650 – 650 K -> D. Constitutively activated kinase.
Mutagenesis 650 – 650 K -> L. Constitutively activated kinase.


Literature citations

Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation.
Hart K.C.; Robertson S.C.; Donoghue D.J.;
Mol. Biol. Cell 12:931-942(2001)
Cited for: FUNCTION IN STIMULATION OF CELL PROLIFERATION; PHOSPHORYLATION OF PIK3R1; PTPN11/SHP2; STAT1; STAT3 AND MAP KINASES; PHOSPHORYLATION AT TYR-724; MUTAGENESIS OF TYR-577; TYR-724; TYR-760 AND TYR-770; CHARACTERIZATION OF VARIANT GLU-650;

FGF receptors ubiquitylation: dependence on tyrosine kinase activity and role in downregulation.
Monsonego-Ornan E.; Adar R.; Rom E.; Yayon A.;
FEBS Lett. 528:83-89(2002)
Cited for: UBIQUITINATION; PHOSPHORYLATION; CATALYTIC ACTIVITY; MUTAGENESIS OF LYS-508; CHARACTERIZATION OF VARIANT ACH ARG-380; CHARACTERIZATION OF VARIANT TD2 GLU-650;

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3.
Agazie Y.M.; Movilla N.; Ischenko I.; Hayman M.J.;
Oncogene 22:6909-6918(2003)
Cited for: FUNCTION AS PROTO-ONCOGENE IN ACTIVATION OF SIGNALING AND CELL PROLIFERATION; FUNCTION IN PHOSPHORYLATION OF FRS2; CHARACTERIZATION OF VARIANT GLU-650; AUTOPHOSPHORYLATION;

Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLCgamma-activated STAT1.
Harada D.; Yamanaka Y.; Ueda K.; Nishimura R.; Morishima T.; Seino Y.; Tanaka H.;
Bone 41:273-281(2007)
Cited for: FUNCTION IN REGULATION OF CHONDROCYTE PROLIFERATION AND IN ACTIVATION OF PLCG1 AND STAT1; INTERACTION WITH FHF1 AND HEPARIN; SUBCELLULAR LOCATION; PHOSPHORYLATION; CHARACTERIZATION OF VARIANTS ARG-380; GLU-650 AND MET-650;

Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins.
Krejci P.; Masri B.; Salazar L.; Farrington-Rock C.; Prats H.; Thompson L.M.; Wilcox W.R.;
J. Biol. Chem. 282:2929-2936(2007)
Cited for: FUNCTION IN PHOSPHORYLATION OF FRS2; CHARACTERIZATION OF VARIANT GLU-650; ACTIVITY REGULATION; CATALYTIC ACTIVITY;

Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.
Tavormina P.L.; Shiang R.; Thompson L.M.; Zhu Y.-Z.; Wilkin D.J.; Lachman R.S.; Wilcox W.R.; Rimoin D.L.; Cohn D.H.; Wasmuth J.J.;
Nat. Genet. 9:321-328(1995)
Cited for: VARIANTS TD1 CYS-248 AND CYS-371; VARIANT TD2 GLU-650;

Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II.
Webster M.K.; D'Avis P.Y.; Robertson S.C.; Donoghue D.J.;
Mol. Cell. Biol. 16:4081-4087(1996)
Cited for: CHARACTERIZATION OF VARIANT TD2 GLU-650; CHARACTERIZATION OF VARIANT GLN-650; PHOSPHORYLATION AT TYR-647 AND TYR-648;

Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.
Chesi M.; Nardini E.; Brents L.A.; Schroeck E.; Ried T.; Kuehl W.M.; Bergsagel P.L.;
Nat. Genet. 16:260-264(1997)
Cited for: INVOLVEMENT IN MULTIPLE MYELOMA; VARIANTS CYS-373; GLU-650 AND MET-650;

Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas.
Cappellen D.; De Oliveira C.; Ricol D.; Gil Diez de Medina S.; Bourdin J.; Sastre-Garau X.; Chopin D.; Thiery J.P.; Radvanyi F.;
Nat. Genet. 23:18-20(1999)
Cited for: VARIANTS BLC CYS-248; CYS-249; CYS-370 AND GLU-650; VARIANTS CERCA CYS-248; CYS-249; CYS-370 AND GLU-650;

Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans.
Logie A.; Dunois-Larde C.; Rosty C.; Levrel O.; Blanche M.; Ribeiro A.; Gasc J.-M.; Jorcano J.; Werner S.; Sastre-Garau X.; Thiery J.P.; Radvanyi F.;
Hum. Mol. Genet. 14:1153-1160(2005)
Cited for: VARIANTS KERSEB CYS-248; CYS-249; CYS-370; CYS-371; CYS-373; GLU-650 AND MET-650;

Patterns of somatic mutation in human cancer genomes.
Greenman C.; Stephens P.; Smith R.; Dalgliesh G.L.; Hunter C.; Bignell G.; Davies H.; Teague J.; Butler A.; Stevens C.; Edkins S.; O'Meara S.; Vastrik I.; Schmidt E.E.; Avis T.; Barthorpe S.; Bhamra G.; Buck G.; Choudhury B.; Clements J.; Cole J.; Dicks E.; Forbes S.; Gray K.; Halliday K.; Harrison R.; Hills K.; Hinton J.; Jenkinson A.; Jones D.; Menzies A.; Mironenko T.; Perry J.; Raine K.; Richardson D.; Shepherd R.; Small A.; Tofts C.; Varian J.; Webb T.; West S.; Widaa S.; Yates A.; Cahill D.P.; Louis D.N.; Goldstraw P.; Nicholson A.G.; Brasseur F.; Looijenga L.; Weber B.L.; Chiew Y.-E.; DeFazio A.; Greaves M.F.; Green A.R.; Campbell P.; Birney E.; Easton D.F.; Chenevix-Trench G.; Tan M.-H.; Khoo S.K.; Teh B.T.; Yuen S.T.; Leung S.Y.; Wooster R.; Futreal P.A.; Stratton M.R.;
Nature 446:153-158(2007)
Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-79; ARG-228; MET-338; LEU-384; ASN-646 AND GLU-650;

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
Goriely A.; Hansen R.M.; Taylor I.B.; Olesen I.A.; Jacobsen G.K.; McGowan S.J.; Pfeifer S.P.; McVean G.A.; Rajpert-De Meyts E.; Wilkie A.O.;
Nat. Genet. 41:1247-1252(2009)
Cited for: VARIANT TGCT GLU-650;

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.