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UniProtKB/Swiss-Prot P25445: Variant p.Thr270Lys

Tumor necrosis factor receptor superfamily member 6
Gene: FAS
Chromosomal location: 10q24.1
Variant information

Variant position:  270
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 Threonine (T) to Lysine (K) at position 270 (T270K, p.Thr270Lys).
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 polar (T) 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:  Autoimmune lymphoproliferative syndrome 1A (ALPS1A) [MIM:601859]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269|PubMed:10090885, ECO:0000269|PubMed:10340403, ECO:0000269|PubMed:10515860, ECO:0000269|PubMed:11418480, ECO:0000269|PubMed:17336828, ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:7540117, ECO:0000269|PubMed:8929361, ECO:0000269|PubMed:9028321, ECO:0000269|PubMed:9028957, ECO:0000269|PubMed:9322534, ECO:0000269|PubMed:9821419, ECO:0000269|PubMed:9927496}. 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 ALPS1A; loss of interaction with FADD.
Any additional useful information about the variant.



Sequence information

Variant position:  270
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  335
The length of the canonical sequence.

Location on the sequence:   RKNGVNEAKIDEIKNDNVQD  T AEQKVQLLRNWHQLHGKKEA
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                         RKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEA

Rhesus macaque                RKNGVSEAKIDEIKNDNVQDTAEQKVQLLRNWYQLHGKKDA

Mouse                         RENNIKEGKIDEIMHDSIQDTAEQKVQLLLCWYQSHGKSDA

Rat                           RQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGA

Pig                           RKNGIEETKIDEIMHDNPKDTAEQKVQLLRNWYLYHGKKDA

Bovine                        RKNGMEEAKIDDIMHDNVHETAEQKVQLLRNWYQSHGKKNA

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 – 335 Tumor necrosis factor receptor superfamily member 6
Topological domain 191 – 335 Cytoplasmic
Domain 230 – 314 Death
Region 212 – 317 Interaction with HIPK3
Alternative sequence 87 – 335 Missing. In isoform 3.
Alternative sequence 104 – 335 Missing. In isoform 2.
Alternative sequence 133 – 335 Missing. In isoform 5.
Alternative sequence 150 – 335 Missing. In isoform 4.
Alternative sequence 221 – 335 Missing. In isoform 7.
Mutagenesis 250 – 250 R -> E. Strongly decreased interaction with FADD.
Mutagenesis 261 – 261 E -> K. Loss of interaction with FADD.
Mutagenesis 283 – 283 Q -> K. Loss of interaction with FADD.
Mutagenesis 287 – 287 K -> D. Strongly decreased interaction with FADD.
Helix 270 – 282


Literature citations

Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations.
Rieux-Laucat F.; Blachere S.; Danielan S.; De Villartay J.P.; Oleastro M.; Solary E.; Bader-Meunier B.; Arkwright P.; Pondare C.; Bernaudin F.; Chapel H.; Nielsen S.; Berrah M.; Fischer A.; Le Deist F.;
Blood 94:2575-2582(1999)
Cited for: VARIANTS ALPS1A LEU-249; PRO-250; ASP-253; SER-253; ARG-259; LYS-270 AND LYS-272;

The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.
Wang L.; Yang J.K.; Kabaleeswaran V.; Rice A.J.; Cruz A.C.; Park A.Y.; Yin Q.; Damko E.; Jang S.B.; Raunser S.; Robinson C.V.; Siegel R.M.; Walz T.; Wu H.;
Nat. Struct. Mol. Biol. 17:1324-1329(2010)
Cited for: CHARACTERIZATION OF VARIANTS ALPS1A CYS-232; GLN-250; ASP-257; TYR-260; VAL-260; LYS-270 AND LYS-272; MUTAGENESIS OF ARG-250; GLU-261; GLN-283 AND LYS-287;

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.