Home  |  Contact

UniProtKB/Swiss-Prot Q9UM47: Variant p.Arg133Cys

Neurogenic locus notch homolog protein 3
Gene: NOTCH3
Chromosomal location: 19p13.1-p13.2
Variant information

Variant position:  133
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Cysteine (C) at position 133 (R133C, p.Arg133Cys).
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 large size and basic (R) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -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

Involvement in disease:  Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 1 (CADASIL1) [MIM:125310]: A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. {ECO:0000269|PubMed:10227618, ECO:0000269|PubMed:10371548, ECO:0000269|PubMed:10802807, ECO:0000269|PubMed:10854111, ECO:0000269|PubMed:11058919, ECO:0000269|PubMed:11102981, ECO:0000269|PubMed:11559313, ECO:0000269|PubMed:11755616, ECO:0000269|PubMed:11810186, ECO:0000269|PubMed:12136071, ECO:0000269|PubMed:12146805, ECO:0000269|PubMed:12589106, ECO:0000269|PubMed:12810003, ECO:0000269|PubMed:15229130, ECO:0000269|PubMed:15300988, ECO:0000269|PubMed:15350543, ECO:0000269|PubMed:15364702, ECO:0000269|PubMed:15378071, ECO:0000269|PubMed:15818833, ECO:0000269|PubMed:16009764, ECO:0000269|PubMed:24000151, ECO:0000269|PubMed:9388399}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In CADASIL1; no effect on ligand-binding; no effect on cell membrane localization; reduced proteolytic processing.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  133
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2321
The length of the canonical sequence.

Location on the sequence:   RGPDCSLPDPCLSSPCAHGA  R CSVGPDGRFLCSCPPGYQGR
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: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         RGPDCSLPDPCLSSPCAHGARCSVGPDGRFLCSCPPGYQGR

Mouse                         QGPDCSQPDPCVSRPCVHGAPCSVGPDGRFACACPPGYQGQ

Rat                           RGPDCSLPDPCFSSPCAHGAPCSVGSDGRYACACPPGYQGR

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.

TypePositionsDescription
Chain 40 – 2321 Neurogenic locus notch homolog protein 3
Topological domain 40 – 1643 Extracellular
Domain 119 – 156 EGF-like 3
Disulfide bond 123 – 134
Disulfide bond 128 – 144


Literature citations

Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
Joutel A.; Vahedi K.; Corpechot C.; Troesch A.; Chabriat H.; Vayssiere C.; Cruaud C.; Maciazek J.; Weissenbach J.; Bousser M.-G.; Bach J.-F.; Tournier-Lasserve E.;
Lancet 350:1511-1515(1997)
Cited for: VARIANTS CADASIL1 TYR-49; CYS-71; CYS-90; CYS-110; CYS-133; CYS-141; ARG-146; CYS-153; CYS-169; CYS-171; CYS-182; ARG-185; SER-212; GLY-222; TYR-224; CYS-258; TYR-542; CYS-558; CYS-578; CYS-728; CYS-985; CYS-1006; CYS-1031; CYS-1231 AND ARG-1261; VARIANTS ARG-170; LEU-496; GLN-1133; MET-1183 AND VAL-2223;

Quantitative MRI in CADASIL: correlation with disability and cognitive performance.
Dichgans M.; Filippi M.; Bruening R.; Iannucci G.; Berchtenbreiter C.; Minicucci L.; Uttner I.; Crispin A.; Ludwig H.; Gasser T.; Yousry T.A.;
Neurology 52:1361-1367(1999)
Cited for: VARIANTS CADASIL1 CYS-90; PHE-117; CYS-133; CYS-141; CYS-169; TYR-174; CYS-182 AND ARG-183;

Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group.
Lesnik Oberstein S.A.J.; Ferrari M.D.; Bakker E.; van Gestel J.; Kneppers A.L.J.; Frants R.R.; Breuning M.H.; Haan J.;
Neurology 52:1913-1915(1999)
Cited for: VARIANTS CADASIL1 CYS-133; CYS-141; CYS-153; CYS-182; CYS-207; CYS-544 AND ARG-1015;

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains.
Dichgans M.; Ludwig H.; Mueller-Hoecker J.; Messerschmidt A.; Gasser T.;
Eur. J. Hum. Genet. 8:280-285(2000)
Cited for: VARIANTS CADASIL1 80-ASP--SER-84 DEL; CYS-90; PHE-93; CYS-110; PHE-117; PHE-123; CYS-133; CYS-141; SER-144; TYR-144; CYS-150; 153-ARG--CYS-155 DEL; CYS-153; CYS-169; TYR-174; CYS-182; ARG-183; SER-183; ARG-185 AND PHE-194;

Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content.
Escary J.-L.; Cecillon M.; Maciazek J.; Lathrop M.; Tournier-Lasserve E.; Joutel A.;
Hum. Mutat. 16:518-526(2000)
Cited for: VARIANTS CADASIL1 TYR-49; CYS-54; CYS-90; CYS-110; 114-GLY--PRO-120 DEL; TYR-123; CYS-133; CYS-141; ARG-146; CYS-153; SER-162; CYS-169; TYR-174; CYS-180; CYS-182; ARG-185; TYR-194; TYR-206; CYS-207; SER-212; GLY-222; TYR-224; CYS-258; TYR-542; CYS-558; CYS-578; CYS-607; CYS-728; CYS-984; CYS-985; CYS-1006; CYS-1031; CYS-1231 AND ARG-1261;

Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.
Joutel A.; Favrole P.; Labauge P.; Chabriat H.; Lescoat C.; Andreux F.; Domenga V.; Cecillon M.; Vahedi K.; Ducros A.; Cave-Riant F.; Bousser M.G.; Tournier-Lasserve E.;
Lancet 358:2049-2051(2001)
Cited for: VARIANTS CADASIL1 CYS-110; CYS-133; TRP-134; CYS-141; CYS-153; CYS-182; GLY-185; CYS-207; SER-212; GLY-222; SER-428; CYS-558; CYS-985 AND CYS-1063;

Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis.
Santa Y.; Uyama E.; Chui D.H.; Arima M.; Kotorii S.; Takahashi K.; Tabira T.;
J. Neurol. Sci. 212:79-84(2003)
Cited for: VARIANTS CADASIL1 CYS-90; CYS-133; CYS-169; ARG-174; PHE-174 AND LYS-213;

Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients.
Opherk C.; Peters N.; Herzog J.; Luedtke R.; Dichgans M.;
Brain 127:2533-2539(2004)
Cited for: VARIANTS CADASIL1 GLY-43; PHE-49; CYS-60; SER-65; TRP-76; 77-GLN--CYS-82 DEL; 80-ASP--SER-84 DEL; ARG-87; TYR-87; CYS-90; PHE-93; TRP-106; TYR-108; CYS-110; PHE-117; PHE-123; CYS-133; TRP-134; CYS-141; SER-144; TYR-144; CYS-145; CYS-149; CYS-150; 153-ARG--155-CYS DEL; CYS-153; SER-155; CYS-169; ARG-174; TYR-174; CYS-182; ARG-183; SER-183; PHE-183; ARG-185; PHE-194; TYR-201; CYS-207; TYR-233; 239-ASP--ASP-253 DEL; SER-240; ARG-245; TYR-260; CYS-332; CYS-335; CYS-337; SER-379; ARG-395; CYS-421; TYR-428; ARG-440; SER-446; TYR-484; TYR-495; ARG-511; TYR-549; CYS-558; CYS-985 AND TYR-1261;

Detection of the founder effect in Finnish CADASIL families.
Mykkaenen K.; Savontaus M.L.; Juvonen V.; Sistonen P.; Tuisku S.; Tuominen S.; Penttinen M.; Lundkvist J.; Viitanen M.; Kalimo H.; Peoyhoenen M.;
Eur. J. Hum. Genet. 12:813-819(2004)
Cited for: VARIANT CADASIL1 CYS-133;

CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk.
Peters N.; Opherk C.; Zacherle S.; Capell A.; Gempel P.; Dichgans M.;
Exp. Cell Res. 299:454-464(2004)
Cited for: CHARACTERIZATION OF VARIANTS CADASIL1 CYS-133; SER-183 AND ARG-455; FUNCTION; SUBCELLULAR LOCATION; LIGAND-BINDING DOMAIN; PROTEOLYTIC PROCESSING;

Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies.
Peters N.; Opherk C.; Bergmann T.; Castro M.; Herzog J.; Dichgans M.;
Arch. Neurol. 62:1091-1094(2005)
Cited for: VARIANTS CADASIL1 GLY-43; PHE-49; CYS-60; SER-65; TRP-76; 80-ASP--SER-84 DEL; ARG-87; CYS-90; PHE-93; TYR-108; CYS-110; PHE-117; PHE-123; CYS-133; TRP-134; CYS-141; SER-144; TYR-144; CYS-149; CYS-150; CYS-153; 153-ARG--CYS-155 DEL; CYS-169; ARG-174; TYR-174; CYS-182; SER-183; PHE-183; ARG-185; PHE-194; CYS-207; TYR-233; SER-240; ARG-245; TYR-260; 239-ASP--ASP-253 DEL; CYS-319; CYS-332; CYS-335; CYS-337; SER-379; ARG-395; CYS-421; TYR-428; ARG-440; PHE-484; TYR-495; ARG-511; TYR-549; CYS-558; CYS-728; SER-775; CYS-985 AND TYR-1261;

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.