UniProtKB/Swiss-Prot P49768: Variant p.Leu282Val

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 282 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 Leucine (L) to Valine (V) at position 282 (L282V, p.Leu282Val). 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: Similar physico-chemical property. Both residues are medium size and hydrophobic. 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
Variant description: In AD3; results in altered amyloid-beta production and increased amyloid-beta 42/amyloid-beta 40 ratio. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63749937 [ dbSNP | Ensembl ]

Sequence information

Variant position: 282 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: LCPKGPLRMLVETAQERNET L FPALIYSSTMVWLVNMAEGD 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.

Literature citations

Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.
Dermaut B.; Kumar-Singh S.; De Jonghe C.; Cruts M.; Loefgren A.; Luebke U.; Cras P.; Dom R.; De Deyn P.P.; Martin J.J.; Van Broeckhoven C.;
Brain 124:2383-2392(2001)
Cited for: VARIANT AD3 VAL-282; CHARACTERIZATION OF VARIANT AD3 VAL-282; A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques.
Dermaut B.; Kumar-Singh S.; Engelborghs S.; Theuns J.; Rademakers R.; Saerens J.; Pickut B.A.; Peeters K.; van den Broeck M.; Vennekens K.; Claes S.; Cruts M.; Cras P.; Martin J.J.; Van Broeckhoven C.; De Deyn P.P.;
Ann. Neurol. 55:617-626(2004)
Cited for: VARIANT PIDB VAL-183; CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282; CHARACTERIZATION OF VARIANT PIDB VAL-183; Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40.
Kumar-Singh S.; Theuns J.; Van Broeck B.; Pirici D.; Vennekens K.; Corsmit E.; Cruts M.; Dermaut B.; Wang R.; Van Broeckhoven C.;
Hum. Mutat. 27:686-695(2006)
Cited for: CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262; PHE-263; VAL-282 AND ALA-384;