UniProtKB/Swiss-Prot P49768: Variant p.Met146Leu

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 146 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 Methionine (M) to Leucine (L) at position 146 (M146L, p.Met146Leu). 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: 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; disease phenotype shows high clinical variability; founder mutation originating from Southern Italy and distributed worldwide; alters the conformation of the active site; slightly increased protease activity with APP; decreased activity for Notch1 cleavage; no loss of its ability to cleave Ephb2/CTF1. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63750306 [ dbSNP | Ensembl ]

Sequence information

Variant position: 146 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: GQRALHSILNAAIMISVIVV M TILLVVLYKYRCYKVIHAWL 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
Transmembrane	133 – 153	Helical
Mutagenesis	131 – 131	H -> R. Severe decrease of protease activity with APP.
Mutagenesis	136 – 136	A -> G. Decreased protease activity with APP.
Mutagenesis	143 – 143	I -> V. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis	150 – 150	L -> P. Nearly abolishes protease activity with APP.
Mutagenesis	165 – 165	W -> G. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Helix	125 – 155

Literature citations

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
Sherrington R.; Rogaev E.I.; Liang Y.; Rogaeva E.A.; Levesque G.; Ikeda M.; Chi H.; Lin C.; Li G.; Holman K.; Tsuda T.; Mar L.; Foncin J.-F.; Bruni A.C.; Montesi M.P.; Sorbi S.; Rainero I.; Pinessi L.; Nee L.; Chumakov I.; Pollen D.; Brookes A.; Sanseau P.; Polinsky R.J.; Wasco W.; da Silva H.A.R.; Haines J.L.; Pericak-Vance M.A.; Tanzi R.E.; Roses A.D.; Fraser P.E.; Rommens J.M.; St George-Hyslop P.H.;
Nature 375:754-760(1995)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2); VARIANTS AD3 LEU-146; ARG-163; GLU-246 AND VAL-286; TISSUE SPECIFICITY; Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.
Campion D.; Dumanchin C.; Hannequin D.; Dubois B.; Belliard S.; Puel M.; Thomas-Anterion C.; Michon A.; Martin C.; Charbonnier F.; Raux G.; Camuzat A.; Penet C.; Mesnage V.; Martinez M.; Clerget-Darpoux F.; Brice A.; Frebourg T.;
Am. J. Hum. Genet. 65:664-670(1999)
Cited for: VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND TYR-410; VARIANT GLY-318; Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.
Rogaeva E.A.; Fafel K.C.; Song Y.Q.; Medeiros H.; Sato C.; Liang Y.; Richard E.; Rogaev E.I.; Frommelt P.; Sadovnick A.D.; Meschino W.; Rockwood K.; Boss M.A.; Mayeux R.; St George-Hyslop P.;
Neurology 57:621-625(2001)
Cited for: VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146; VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178; ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235; PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418; GLU-431; PHE-435 AND VAL-439; VARIANT GLY-318; 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; Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.
Bruni A.C.; Bernardi L.; Colao R.; Rubino E.; Smirne N.; Frangipane F.; Terni B.; Curcio S.A.; Mirabelli M.; Clodomiro A.; Di Lorenzo R.; Maletta R.; Anfossi M.; Gallo M.; Geracitano S.; Tomaino C.; Muraca M.G.; Leotta A.; Lio S.G.; Pinessi L.; Rainero I.; Sorbi S.; Nee L.; Milan G.; Pappata S.; Postiglione A.; Abbamondi N.; Forloni G.; St George Hyslop P.; Rogaeva E.; Bugiani O.; Giaccone G.; Foncin J.F.; Spillantini M.G.; Puccio G.;
Neurology 74:798-806(2010)
Cited for: VARIANT AD3 LEU-146; 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; 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;