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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P22607: Variant p.Lys650Met

Fibroblast growth factor receptor 3
Gene: FGFR3
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Variant information Variant position: help 650 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help LP/P [Disclaimer] 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: help From Lysine (K) to Methionine (M) at position 650 (K650M, p.Lys650Met). 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: help Change from large size and basic (K) to medium size and hydrophobic (M) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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
Variant description: help In KERSEB, ACH, TD1 and SADDAN; constitutively activated kinase with impaired internalization and degradation, resulting in prolonged FGFR3 signaling. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 650 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 806 The length of the canonical sequence.
Location on the sequence: help 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: help 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: help 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
A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.
Tavormina P.L.; Bellus G.A.; Webster M.K.; Bamshad M.J.; Fraley A.E.; McIntosh I.; Szabo J.; Jiang W.; Jabs E.W.; Wilcox W.R.; Wasmuth J.J.; Donoghue D.J.; Thompson L.M.; Francomano C.A.;
Am. J. Hum. Genet. 64:722-731(1999)
Cited for: INVOLVEMENT IN SADDAN; VARIANT SADDAN MET-650; CHARACTERIZATION OF VARIANT SADDAN MET-650; 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; The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor.
Bonaventure J.; Horne W.C.; Baron R.;
FEBS J. 274:3078-3093(2007)
Cited for: FUNCTION IN PHOSPHORYLATION OF CBL; UBIQUITINATION; GLYCOSYLATION; SUBCELLULAR LOCATION; ACTIVITY REGULATION; CHARACTERIZATION OF VARIANTS CYS-248; CYS-373 AND MET-650; 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; Lys650Met substitution in the tyrosine kinase domain of the fibroblast growth factor receptor gene causes thanatophoric dysplasia type I.
Kitoh H.; Brodie S.G.; Kupke K.G.; Lachman R.S.; Wilcox W.R.;
Hum. Mutat. 12:362-363(1998)
Cited for: VARIANT TD1 MET-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;
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.