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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P05067: Variant p.Val717Ile

Amyloid-beta precursor protein
Gene: APP
Variant information Variant position: help 717 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 Valine (V) to Isoleucine (I) at position 717 (V717I, p.Val717Ile). 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 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: help 3 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 AD1; increased amyloid-beta protein 42/40 ratio. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.

Sequence information Variant position: help 717 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 770 The length of the canonical sequence.
Location on the sequence: help SNKGAIIGLMVGGVVIATVI V ITLVMLKKKQYTSIHHGVVE 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.







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.
Chain 18 – 770 Amyloid-beta precursor protein
Chain 672 – 770 C99
Chain 688 – 770 C83
Chain 691 – 770 C80
Chain 712 – 770 Gamma-secretase C-terminal fragment 59
Chain 714 – 770 Gamma-secretase C-terminal fragment 57
Transmembrane 702 – 722 Helical
Region 695 – 722 Interaction with PSEN1
Site 704 – 704 Implicated in free radical propagation
Site 706 – 706 Susceptible to oxidation
Modified residue 729 – 729 Phosphothreonine
Modified residue 730 – 730 Phosphoserine; by APP-kinase I
Alternative sequence 306 – 770 Missing. In isoform APP305.
Mutagenesis 704 – 704 G -> V. Reduced protein oxidation. No hippocampal neuron toxicity.
Mutagenesis 706 – 706 M -> L. Reduced lipid peroxidation inhibition.
Mutagenesis 706 – 706 M -> V. No free radical production. No hippocampal neuron toxicity.
Mutagenesis 717 – 717 V -> CS. Unchanged amyloid-beta protein 42/total amyloid-beta ratio.
Mutagenesis 717 – 717 V -> K. Decreased amyloid-beta protein 42/total amyloid-beta ratio.
Mutagenesis 717 – 717 V -> M. Increased amyloid-beta protein 42/40 ratio. No change in apoptosis after caspase cleavage.
Mutagenesis 728 – 728 Y -> A. No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in amyloid-beta protein 42 secretion.

Literature citations
A system for studying the effect(s) of familial Alzheimer disease mutations on the processing of the beta-amyloid peptide precursor.
Denman R.B.; Rosenzcwaig R.; Miller D.L.;
Biochem. Biophys. Res. Commun. 192:96-103(1993)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 655-737; VARIANTS AD1 GLY-717; ILE-717 AND PHE-717; Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
Goate A.; Chartier-Harlin M.-C.; Mullan M.; Brown J.; Crawford F.; Fidani L.; Giuffra L.; Haynes A.; Irving N.; James L.; Mant R.; Newton P.; Rooke K.; Roques P.; Talbot C.; Pericak-Vance M.; Roses A.D.; Williamson R.; Rossor M.; Owen M.; Hardy J.;
Nature 349:704-706(1991)
Cited for: VARIANT AD1 ILE-717; The 717Val-->Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups.
Yoshioka K.; Miki T.; Katsuya T.; Ogihara T.; Sakaki Y.;
Biochem. Biophys. Res. Commun. 178:1141-1146(1991)
Cited for: VARIANT AD1 ILE-717; Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease.
Naruse S.; Igarashi S.; Kobayashi H.; Aoki K.; Inuzuka T.; Kaneko K.; Shimizu T.; Iihara K.; Kojima T.; Miyatake T.; Tsuji S.;
Lancet 337:978-979(1991)
Cited for: VARIANT AD1 ILE-717; Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations.
Liepnieks J.J.; Ghetti B.; Farlow M.; Roses A.D.; Benson M.D.;
Biochem. Biophys. Res. Commun. 197:386-392(1993)
Cited for: VARIANTS AD1 ILE-717 AND PHE-717; A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease.
Brooks W.S.; Martins R.N.; De Voecht J.; Nicholson G.A.; Schofield P.R.; Kwok J.B.J.; Fisher C.; Yeung L.U.; Van Broeckhoven C.;
Neurosci. Lett. 199:183-186(1995)
Cited for: VARIANT AD1 ILE-717; Familial Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43).
Maruyama K.; Tomita T.; Shinozaki K.; Kume H.; Asada H.; Saido T.C.; Ishiura S.; Iwatsubo T.; Obata K.;
Biochem. Biophys. Res. Commun. 227:730-735(1996)
Cited for: CHARACTERIZATION OF VARIANTS AD1 GLY-717; ILE-717 AND PHE-717; MUTAGENESIS OF VAL-717; High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.
Finckh U.; Mueller-Thomsen T.; Mann U.; Eggers C.; Marksteiner J.; Meins W.; Binetti G.; Alberici A.; Hock C.; Nitsch R.M.; Gal A.;
Am. J. Hum. Genet. 66:110-117(2000)
Cited for: VARIANT AD1 ILE-717; Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.
Kumar-Singh S.; De Jonghe C.; Cruts M.; Kleinert R.; Wang R.; Mercken M.; De Strooper B.; Vanderstichele H.; Loefgren A.; Vanderhoeven I.; Backhovens H.; Vanmechelen E.; Kroisel P.M.; Van Broeckhoven C.;
Hum. Mol. Genet. 9:2589-2598(2000)
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.