UniProtKB/Swiss-Prot P49768: Variant p.Glu280Gly

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 280 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: LP/P [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.] 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: From Glutamate (E) to Glycine (G) at position 280 (E280G, p.Glu280Gly). 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 glycine (G) 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
Variant description: In AD3; some AD3 patients manifest spastic paraparesis and unusual amyloid plaques with prominent amyloid angiopathy on brain biopsy; decreased protease activity with APP; increased amyloid-beta 42/amyloid-beta 40 ratio; impaired ability to cleave Ephb2/CTF1. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63750231 [ dbSNP | Ensembl ]

Sequence information

Variant position: 280 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 467 The length of the canonical sequence.
Location on the sequence: 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: 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 – 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; Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.
O'Riordan S.; McMonagle P.; Janssen J.C.; Fox N.C.; Farrell M.; Collinge J.; Rossor M.N.; Hutchinson M.;
Neurology 59:1108-1110(2002)
Cited for: VARIANT AD3 GLY-280; Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor.
Litterst C.; Georgakopoulos A.; Shioi J.; Ghersi E.; Wisniewski T.; Wang R.; Ludwig A.; Robakis N.K.;
J. Biol. Chem. 282:16155-16163(2007)
Cited for: CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260; LEU-264 AND GLY-280; FUNCTION; MUTAGENESIS OF ASP-257; 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;