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UniProtKB/Swiss-Prot Q13485: Variant p.Ile500Val

Mothers against decapentaplegic homolog 4
Gene: SMAD4
Variant information

Variant position:  500
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 Isoleucine (I) to Valine (V) at position 500 (I500V, p.Ile500Val).
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:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
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:  Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. {ECO:0000269|PubMed:22158539, ECO:0000269|PubMed:22243968}. 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 MYHRS.
Any additional useful information about the variant.

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

Sequence information

Variant position:  500
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  552
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.






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 – 552 Mothers against decapentaplegic homolog 4
Domain 323 – 552 MH2
Site 515 – 515 Necessary for heterotrimerization
Modified residue 507 – 507 N6-acetyllysine
Cross 519 – 519 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Mutagenesis 496 – 496 R -> S. No effect on heterotrimerization. Partially diminished transcriptional activation.
Mutagenesis 502 – 502 R -> S. No effect on heterotrimerization. Greatly reduced transcriptional activation.
Mutagenesis 515 – 515 R -> S. Reduced heterotrimerization.
Mutagenesis 519 – 519 K -> R. Abolishes ubiquitination.
Beta strand 500 – 506

Literature citations

A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.
Caputo V.; Cianetti L.; Niceta M.; Carta C.; Ciolfi A.; Bocchinfuso G.; Carrani E.; Dentici M.L.; Biamino E.; Belligni E.; Garavelli L.; Boccone L.; Melis D.; Andria G.; Gelb B.D.; Stella L.; Silengo M.; Dallapiccola B.; Tartaglia M.;
Am. J. Hum. Genet. 90:161-169(2012)
Cited for: VARIANTS MYHRS THR-500 AND VAL-500;

Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.
Le Goff C.; Mahaut C.; Abhyankar A.; Le Goff W.; Serre V.; Afenjar A.; Destree A.; di Rocco M.; Heron D.; Jacquemont S.; Marlin S.; Simon M.; Tolmie J.; Verloes A.; Casanova J.L.; Munnich A.; Cormier-Daire V.;
Nat. Genet. 44:85-88(2012)

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.