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UniProtKB/Swiss-Prot P10721: Variant p.Asp816Val

Mast/stem cell growth factor receptor Kit
Gene: KIT
Variant information

Variant position:  816
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 Aspartate (D) to Valine (V) at position 816 (D816V, p.Asp816Val).
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 medium size and acidic (D) to medium size and hydrophobic (V)
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:  Mastocytosis, cutaneous (MASTC) [MIM:154800]: A form of mastocytosis, a heterogeneous group of disorders associated with abnormal proliferation and accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. MASTC is an autosomal dominant form characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed Darier sign. {ECO:0000269|PubMed:15173254, ECO:0000269|PubMed:19865100, ECO:0000269|PubMed:21689725, ECO:0000269|PubMed:24289326, ECO:0000269|PubMed:9990072}. 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:  Mastocytosis, systemic (MASTSYS) [MIM:154800]: A severe form of mastocytosis characterized by abnormal proliferation and accumulation of mast cells in several organs, resulting in a systemic disease that may affect bone, gastrointestinal tract, lymphatics, spleen, and liver. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. It can also lead to mast cell leukemia, which carries a high risk of mortality. {ECO:0000269|PubMed:9990072}. 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 MASTSYS, MASTC and mast cell leukemia; somatic mutation; constitutively activated; loss of interaction with MPDZ.
Any additional useful information about the variant.

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



Sequence information

Variant position:  816
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  976
The length of the canonical sequence.

Location on the sequence:   RNILLTHGRITKICDFGLAR  D IKNDSNYVVKGNARLPVKWM
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                         RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

                              RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Mouse                         RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

Pig                           RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Bovine                        RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Goat                          RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Cat                           RNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWM

Chicken                       RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

Xenopus laevis                RNILLTHGRITKICDFGLARDIRNDSNYVVKGNARLPVKWM

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 26 – 976 Mast/stem cell growth factor receptor Kit
Topological domain 546 – 976 Cytoplasmic
Domain 589 – 937 Protein kinase
Metal binding 797 – 797 Magnesium
Metal binding 810 – 810 Magnesium
Binding site 796 – 796 ATP
Modified residue 821 – 821 Phosphoserine
Modified residue 823 – 823 Phosphotyrosine; by autocatalysis
Alternative sequence 414 – 976 Missing. In isoform 3.
Mutagenesis 823 – 823 Y -> F. No decrease in activity. Leads to autophosphorylation at Tyr-900.


Literature citations

The direct association of the multiple PDZ domain containing proteins (MUPP-1) with the human c-Kit C-terminus is regulated by tyrosine kinase activity.
Mancini A.; Koch A.; Stefan M.; Niemann H.; Tamura T.;
FEBS Lett. 482:54-58(2000)
Cited for: INTERACTION WITH MPDZ; CHARACTERIZATION OF VARIANT VAL-816; MUTAGENESIS OF LYS-623;

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal.
Voisset E.; Lopez S.; Dubreuil P.; De Sepulveda P.;
Blood 110:2593-2599(2007)
Cited for: INTERACTION WITH FES/FPS; CHARACTERIZATION OF VARIANT VAL-816;

The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction.
Sun J.; Pedersen M.; Ronnstrand L.;
J. Biol. Chem. 284:11039-11047(2009)
Cited for: FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS AND CELL SURVIVAL; FUNCTION IN PHOSPHORYLATION OF CBL; PHOSPHORYLATION AT TYR-568; TYR-703; TYR-721 AND TYR-936; UBIQUITINATION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT VAL-816;

Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816.
Kim S.Y.; Kang J.J.; Lee H.H.; Kang J.J.; Kim B.; Kim C.G.; Park T.K.; Kang H.;
Biochem. Biophys. Res. Commun. 410:224-228(2011)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ACTIVITY REGULATION; AUTOPHOSPHORYLATION; SUBUNIT; CHARACTERIZATION OF VARIANT VAL-816;

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.
Gajiwala K.S.; Wu J.C.; Christensen J.; Deshmukh G.D.; Diehl W.; DiNitto J.P.; English J.M.; Greig M.J.; He Y.A.; Jacques S.L.; Lunney E.A.; McTigue M.; Molina D.; Quenzer T.; Wells P.A.; Yu X.; Zhang Y.; Zou A.; Emmett M.R.; Marshall A.G.; Zhang H.M.; Demetri G.D.;
Proc. Natl. Acad. Sci. U.S.A. 106:1542-1547(2009)
Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 544-935 IN COMPLEX WITH SUNITINIB; CATALYTIC ACTIVITY; AUTOPHOSPHORYLATION; CHARACTERIZATION OF VARIANTS HIS-816 AND VAL-816; ACTIVITY REGULATION;

Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.
Furitsu T.; Tsujimura T.; Tono T.; Ikeda H.; Kitayama H.; Koshimizu U.; Sugahara H.; Butterfield J.H.; Ashman L.K.; Kanayama Y.; Matsuzawa Y.; Kitamura Y.; Kanakura Y.;
J. Clin. Invest. 92:1736-1744(1993)
Cited for: VARIANT MAST CELL LEUKEMIA VAL-816;

Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis.
Longley B.J. Jr.; Metcalfe D.D.; Tharp M.; Wang X.; Tyrrell L.; Lu S.-Z.; Heitjan D.; Ma Y.;
Proc. Natl. Acad. Sci. U.S.A. 96:1609-1614(1999)
Cited for: VARIANTS MASTSYS VAL-816 AND TYR-816; VARIANTS MASTC PHE-816 AND LYS-839; CHARACTERIZATION OF VARIANTS MASTSYS VAL-816 AND TYR-816; CHARACTERIZATION OF VARIANTS MASTC PHE-816 AND LYS-839; INVOLVEMENT IN MASTSYS AND MASTC;

Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations.
Bodemer C.; Hermine O.; Palmerini F.; Yang Y.; Grandpeix-Guyodo C.; Leventhal P.S.; Hadj-Rabia S.; Nasca L.; Georgin-Lavialle S.; Cohen-Akenine A.; Launay J.M.; Barete S.; Feger F.; Arock M.; Catteau B.; Sans B.; Stalder J.F.; Skowron F.; Thomas L.; Lorette G.; Plantin P.; Bordigoni P.; Lortholary O.; de Prost Y.; Moussy A.; Sobol H.; Dubreuil P.;
J. Invest. Dermatol. 130:804-815(2010)
Cited for: VARIANT LEU-541; VARIANTS MASTC ILE-816; TYR-816 AND VAL-816; CHARACTERIZATION OF VARIANTS MASTC ILE-816; TYR-816 AND VAL-816;

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.