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UniProtKB/Swiss-Prot P57727: Variant p.Trp251Cys

Transmembrane protease serine 3
Gene: TMPRSS3
Variant information

Variant position:  251
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 Tryptophan (W) to Cysteine (C) at position 251 (W251C, p.Trp251Cys).
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 aromatic (W) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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:  Deafness, autosomal recessive, 8 (DFNB8) [MIM:601072]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:11424922, ECO:0000269|PubMed:11462234, ECO:0000269|PubMed:11907649, ECO:0000269|PubMed:12393794, ECO:0000269|PubMed:15447792, ECO:0000269|PubMed:16021470}. 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 DFNB8; fails to undergo proteolytic cleavage and is unable to activate ENaC.
Any additional useful information about the variant.

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



Sequence information

Variant position:  251
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  454
The length of the canonical sequence.

Location on the sequence:   QASLQFQGYHLCGGSVITPL  W IITAAHCVYDLYLPKSWTIQ
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                         QASLQFQGYHLCGGSVITPLWIITAAHCVYDLYLPKSWTIQ

Mouse                         QVSLQFQGYHLCGGSIITPLWIVTAAHCVYDLYHPKSWTVQ

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 1 – 454 Transmembrane protease serine 3
Topological domain 70 – 454 Extracellular
Domain 217 – 449 Peptidase S1
Active site 257 – 257 Charge relay system
Disulfide bond 207 – 324
Disulfide bond 242 – 258


Literature citations

The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro.
Guipponi M.; Vuagniaux G.; Wattenhofer M.; Shibuya K.; Vazquez M.; Dougherty L.; Scamuffa N.; Guida E.; Okui M.; Rossier C.; Hancock M.; Buchet K.; Reymond A.; Hummler E.; Marzella P.L.; Kudoh J.; Shimizu N.; Scott H.S.; Antonarakis S.E.; Rossier B.C.;
Hum. Mol. Genet. 11:2829-2836(2002)
Cited for: SUBCELLULAR LOCATION; AUTOCATALYTIC CLEAVAGE; MUTAGENESIS OF SER-401; CHARACTERIZATION OF VARIANTS DFNB8 GLY-103; TRP-109; PHE-194; CYS-251; LEU-404 AND ARG-407; FUNCTION IN ENAC CLEAVAGE;

Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non-syndromic autosomal recessive deafness.
Masmoudi S.; Antonarakis S.E.; Schwede T.; Ghorbel A.M.; Gratri M.; Pappasavas M.P.; Drira M.; Elgaied-Boulila A.; Wattenhofer M.; Rossier C.; Scott H.S.; Ayadi H.; Guipponi M.;
Hum. Mutat. 18:101-108(2001)
Cited for: VARIANTS DFNB8 CYS-251 AND LEU-404;

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.