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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P49768: Variant p.Glu280Ala

Presenilin-1
Gene: PSEN1
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Variant information Variant position: help 280 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help LP/P [Disclaimer] The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change: help From Glutamate (E) to Alanine (A) at position 280 (E280A, p.Glu280Ala). 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: help Change from medium size and acidic (E) to small size and hydrophobic (A) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help -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

Variant description: help In AD3; strong deposition of amyloid-beta 42 is observed in brain regions of AD3 patients; decreased protease activity with APP resulting in altered amyloid-beta production and increased amyloid-beta 42/amyloid-beta 40 ratio; decreased activity for Notch1 cleavage. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 280 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 467 The length of the canonical sequence.
Location on the sequence: help AVLCPKGPLRMLVETAQERN E TLFPALIYSSTMVWLVNMAE 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.
Sequence annotation in neighborhood: help 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 – 298 Presenilin-1 NTF subunit
Topological domain 273 – 380 Cytoplasmic
Alternative sequence 185 – 467 Missing. In isoform 4.
Alternative sequence 257 – 289 Missing. In isoform 7.
Mutagenesis 272 – 272 V -> A. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 273 – 273 E -> A. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 278 – 278 R -> K. Nearly abolishes protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis 284 – 284 P -> S. No significant change of protease activity with APP.
Mutagenesis 286 – 286 L -> AEPQRW. Increases production of amyloid-beta in APP processing.
Mutagenesis 286 – 286 L -> ER. Reduces production of NICD in NOTCH1 processing.
Mutagenesis 291 – 291 T -> P. Abolishes protease activity with APP.
Mutagenesis 292 – 292 M -> D. Loss of endoproteolytic cleavage.
Beta strand 278 – 280



Literature citations
The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.
Clark R.F.; Hutton M.; Fuldner R.A.; Froelich S.; Karran E.; Talbot C.; Crook R.; Lendon C.L.; Prihar G.; He C.; Korenblat K.; Martinez A.; Wragg M.; Busfield F.; Behrens M.I.; Myers A.; Norton J.; Morris J.; Mehta N.; Pearson C.; Lincoln S.; Baker M.; Duff K.; Zehr C.; Perez-Tur J.; Houlden H.; Ruiz A.; Ossa J.; Lopera F.; Arcos M.; Madrigal L.; Collinge J.; Humphreys C.; Asworth T.; Sarner S.; Fox N.C.; Harvey R.; Kennedy A.; Roques P.K.; Cline R.T.; Phillips C.A.; Venter J.C.; Forsel L.; Axelman K.; Lilius L.; Johnston J.; Cowburn R.; Viitanen M.; Winblad B.; Kosik K.S.; Haltia M.; Poyhonen M.; Dickson D.; Mann D.; Neary D.; Snowden J.; Lantos P.; Lannfelt L.; Rossor M.N.; Roberts G.W.; Adams M.D.; Hardy J.; Goate A.M.;
Nat. Genet. 11:219-222(1995)
Cited for: VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280; The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology.
Lemere C.A.; Lopera F.; Kosik K.S.; Lendon C.L.; Ossa J.; Saido T.C.; Yamaguchi H.; Ruiz A.; Martinez A.; Madrigal L.; Hincapie L.; Arango J.C.; Anthony D.C.; Koo E.H.; Goate A.M.; Selkoe D.J.; Arango J.C.;
Nat. Med. 2:1146-1150(1996)
Cited for: VARIANT AD3 ALA-280; INVOLVEMENT IN AD3; E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles.
Lendon C.L.; Martinez A.; Behrens I.M.; Kosik K.S.; Madrigal L.; Norton J.; Neuman R.; Myers A.; Busfield F.; Wragg M.; Arcos M.; Arango-Viana J.C.; Ossa J.; Ruiz A.; Goate A.M.; Lopera F.;
Hum. Mutat. 10:186-195(1997)
Cited for: VARIANT AD3 ALA-280; Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia.
Arango D.; Cruts M.; Torres O.; Backhovens H.; Serrano M.L.; Villareal E.; Montanes P.; Matallana D.; Cano C.; Van Broeckhoven C.; Jacquier M.;
Am. J. Med. Genet. 103:138-143(2001)
Cited for: VARIANTS AD3 MET-94; THR-143 AND ALA-280; VARIANT GLY-318; Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of gamma-secretase.
Chau D.M.; Crump C.J.; Villa J.C.; Scheinberg D.A.; Li Y.M.;
J. Biol. Chem. 287:17288-17296(2012)
Cited for: CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280; A novel PSEN1 K311R mutation discovered in Chinese families with late-onset Alzheimer's disease affects amyloid-beta production and tau phosphorylation.
Dong J.; Qin W.; Wei C.; Tang Y.; Wang Q.; Jia J.;
J. Alzheimers Dis. 57:613-623(2017)
Cited for: VARIANT ARG-311; CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311; FUNCTION; Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase.
Sun L.; Zhou R.; Yang G.; Shi Y.;
Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017)
Cited for: CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89; SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120; ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154; ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174; LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209; LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235; PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262; ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275; ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378; VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405; THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439; CHARACTERIZATION OF VARIANT CMD1U GLY-333; MUTAGENESIS OF THR-99; PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143; LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214; LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248; TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365; ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437;
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.