Variant position:  650

Type of variant:  LP/P [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.]

Residue change:  From Lysine (K) to Glutamate (E) at position 650 (K650E, p.Lys650Glu).

Physico-chemical properties:  Change from large size and basic (K) to medium size and acidic (E)

BLOSUM score:  1

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.

Other resources:  

• Variant rs78311289 [ dbSNP | Ensembl ]

Variant position:  650

Protein sequence length:  806

Location on the sequence:   VMKIADFGLARDVHNLDYYK  K TTNGRLPVKWMAPEALFDRV

Residue conservation: 

Human                         VMKIADFGLARDVHNLDYYKKTTNGRLPVKWMAPEALFDRV

Mouse                         VMKIADFGLARDVHNLDYYKKTTNGRLPVKWMAPEALFDRV

Chicken                       VMKIADFGLARDVHNIDYYKKTTNGRLPVKWMAPEALFDRV

Xenopus laevis                VMKIADFGLARDIHNIDYYKKTTNGRLPVKWMAPEALFDRI

Zebrafish                     VMKIADFGLARDVHNIDYYKKTTNGRLPVKWMAPEALFDRV

Sequence annotation in neighborhood:  

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;