UniProtKB/SwissProt variant VAR

Variant information

Variant position:

425

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 Glutamate (E) to Lysine (K) at position 425 (E425K, p.Glu425Lys).

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 (E) to large size and basic (K)

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:

Melanoma, cutaneous malignant 8 (CMM8) [MIM:614456]: A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:22012259, ECO:0000269|PubMed:22080950}. Note=Disease susceptibility is associated with variations 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 CMM8; associated with disease susceptibility; also associated with pheochromocytomas and paragangliomas susceptibility; results in impaired sumoylation.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs149617956 [ dbSNP | Ensembl ]

Sequence information

Variant position:

425

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

Protein sequence length:

526

The length of the canonical sequence.

Location on the sequence:

SLIPSTGLCSPDLVNRIIKQ E PVLENCSQDLLQHHADLTCT

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                         SLIPSTGLCSPDLVNRIIKQEPVLENCSQDLLQHHADLTCT

Mouse                         SLIPSTGLCSPDLVNRIIKQEPVLENCSQELVQHQADLTCT

Rat                           SLIPSTGLCSPDLVNRIIKQEPVLENCSQELVQHQADLTCT

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.

Type	Positions	Description
Chain	1 – 526	Microphthalmia-associated transcription factor
Region	401 – 431	DNA binding regulation
Modified residue	405 – 405	Phosphoserine; by GSK3
Modified residue	414 – 414	Phosphoserine
Cross	423 – 423	Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Mutagenesis	405 – 405	S -> AP. Loss of phosphorylation and function.
Mutagenesis	423 – 423	K -> R. Loss of sumoylation; when associated with R-289.

Literature citations

The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.
Castro-Vega L.J.; Kiando S.R.; Burnichon N.; Buffet A.; Amar L.; Simian C.; Berdelou A.; Galan P.; Schlumberger M.; Bouatia-Naji N.; Favier J.; Bressac-de Paillerets B.; Gimenez-Roqueplo A.P.;
J. Clin. Endocrinol. Metab. 101:4764-4768(2016)
Cited for: INVOLVEMENT IN DISEASE; VARIANT LYS-425;

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
Bertolotto C.; Lesueur F.; Giuliano S.; Strub T.; de Lichy M.; Bille K.; Dessen P.; d'Hayer B.; Mohamdi H.; Remenieras A.; Maubec E.; de la Fouchardiere A.; Molinie V.; Vabres P.; Dalle S.; Poulalhon N.; Martin-Denavit T.; Thomas L.; Andry-Benzaquen P.; Dupin N.; Boitier F.; Rossi A.; Perrot J.L.; Labeille B.; Robert C.; Escudier B.; Caron O.; Brugieres L.; Saule S.; Gardie B.; Gad S.; Richard S.; Couturier J.; Teh B.T.; Ghiorzo P.; Pastorino L.; Puig S.; Badenas C.; Olsson H.; Ingvar C.; Rouleau E.; Lidereau R.; Bahadoran P.; Vielh P.; Corda E.; Blanche H.; Zelenika D.; Galan P.; Aubin F.; Bachollet B.; Becuwe C.; Berthet P.; Bignon Y.J.; Bonadona V.; Bonafe J.L.; Bonnet-Dupeyron M.N.; Cambazard F.; Chevrant-Breton J.; Coupier I.; Dalac S.; Demange L.; d'Incan M.; Dugast C.; Faivre L.; Vincent-Fetita L.; Gauthier-Villars M.; Gilbert B.; Grange F.; Grob J.J.; Humbert P.; Janin N.; Joly P.; Kerob D.; Lasset C.; Leroux D.; Levang J.; Limacher J.M.; Livideanu C.; Longy M.; Lortholary A.; Stoppa-Lyonnet D.; Mansard S.; Mansuy L.; Marrou K.; Mateus C.; Maugard C.; Meyer N.; Nogues C.; Souteyrand P.; Venat-Bouvet L.; Zattara H.; Chaudru V.; Lenoir G.M.; Lathrop M.; Davidson I.; Avril M.F.; Demenais F.; Ballotti R.; Bressac-de Paillerets B.;
Nature 480:94-98(2011)
Cited for: INVOLVEMENT IN CMM8; VARIANT CMM8 LYS-425;

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
Yokoyama S.; Woods S.L.; Boyle G.M.; Aoude L.G.; MacGregor S.; Zismann V.; Gartside M.; Cust A.E.; Haq R.; Harland M.; Taylor J.C.; Duffy D.L.; Holohan K.; Dutton-Regester K.; Palmer J.M.; Bonazzi V.; Stark M.S.; Symmons J.; Law M.H.; Schmidt C.; Lanagan C.; O'Connor L.; Holland E.A.; Schmid H.; Maskiell J.A.; Jetann J.; Ferguson M.; Jenkins M.A.; Kefford R.F.; Giles G.G.; Armstrong B.K.; Aitken J.F.; Hopper J.L.; Whiteman D.C.; Pharoah P.D.; Easton D.F.; Dunning A.M.; Newton-Bishop J.A.; Montgomery G.W.; Martin N.G.; Mann G.J.; Bishop D.T.; Tsao H.; Trent J.M.; Fisher D.E.; Hayward N.K.; Brown K.M.;
Nature 480:99-103(2011)
Cited for: INVOLVEMENT IN CMM8; VARIANT CMM8 LYS-425; CHARACTERIZATION OF VARIANT CMM8 LYS-425;

UniProtKB/Swiss-Prot O75030: Variant p.Glu425Lys