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UniProtKB/Swiss-Prot P22607: Variant p.Lys650Met

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 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:  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:  -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:  Achondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. ACH is an autosomal dominant disease. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586, ECO:0000269|PubMed:8599935}. 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:  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:  Achondroplasia, severe, with developmental delay and acanthosis nigricans (SADDAN) [MIM:616482]: A severe form of achondroplasia associated with developmental delay and acanthosis nigricans. Patients manifest short-limb dwarfism, with a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Acanthosis nigricans is a skin condition characterized by brown-pigmented, velvety verrucosities in body folds and creases. {ECO:0000269|PubMed:10053006}. 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:  Thanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. 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.

Variant description:  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:  
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

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.