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UniProtKB/Swiss-Prot P22681: Variant p.Lys382Glu

E3 ubiquitin-protein ligase CBL
Gene: CBL
Variant information

Variant position:  382
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 382 (K382E, p.Lys382Glu).
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:  Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. {ECO:0000269|PubMed:20619386, ECO:0000269|PubMed:25178484}. 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 NSLL; dominant-negative; impairs CBL-mediated ubiquitination, internalization and degradation of the EGF receptor/EGFR; decreases the ability to negatively regulate EGFR signaling.
Any additional useful information about the variant.

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

Sequence information

Variant position:  382
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  906
The length of the canonical sequence.

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.



Fission yeast                 --------------SALDMILRCCKSNSHV---VAGHDLYG

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.

Chain 1 – 906 E3 ubiquitin-protein ligase CBL
Zinc finger 381 – 420 RING-type
Region 358 – 906 Required for ubiquitination of SPRED2
Compositional bias 357 – 476 Asp/Glu-rich (acidic)
Modified residue 371 – 371 Phosphotyrosine; by INSR
Mutagenesis 371 – 371 Y -> F. Strongly reduces tyrosine phosphorylation by INSR; when associated with F-700 and F-774.
Mutagenesis 381 – 381 C -> A. Loss of ubiquitin ligase activity.
Turn 382 – 384

Literature citations

Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.
Martinelli S.; De Luca A.; Stellacci E.; Rossi C.; Checquolo S.; Lepri F.; Caputo V.; Silvano M.; Buscherini F.; Consoli F.; Ferrara G.; Digilio M.C.; Cavaliere M.L.; van Hagen J.M.; Zampino G.; van der Burgt I.; Ferrero G.B.; Mazzanti L.; Screpanti I.; Yntema H.G.; Nillesen W.M.; Savarirayan R.; Zenker M.; Dallapiccola B.; Gelb B.D.; Tartaglia M.;
Am. J. Hum. Genet. 87:250-257(2010)

RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR.
Brand K.; Kentsch H.; Glashoff C.; Rosenberger G.;
Hum. Mutat. 35:1372-1381(2014)

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.