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UniProtKB/Swiss-Prot O15118: Variant p.Cys177Tyr

NPC intracellular cholesterol transporter 1
Gene: NPC1
Variant information

Variant position:  177
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 Cysteine (C) to Tyrosine (Y) at position 177 (C177Y, p.Cys177Tyr).
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 polar (C) to large size and aromatic (Y)
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

Involvement in disease:  Niemann-Pick disease C1 (NPC1) [MIM:257220]: A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected. {ECO:0000269|PubMed:10480349, ECO:0000269|PubMed:10521290, ECO:0000269|PubMed:10521297, ECO:0000269|PubMed:11182931, ECO:0000269|PubMed:11333381, ECO:0000269|PubMed:11349231, ECO:0000269|PubMed:11479732, ECO:0000269|PubMed:11545687, ECO:0000269|PubMed:11754101, ECO:0000269|PubMed:12401890, ECO:0000269|PubMed:12408188, ECO:0000269|PubMed:12554680, ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15774455, ECO:0000269|PubMed:16098014, ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:16802107, ECO:0000269|PubMed:27238017, ECO:0000269|PubMed:9211849, ECO:0000269|PubMed:9634529}. 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 NPC1.
Any additional useful information about the variant.

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

Sequence information

Variant position:  177
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1278
The length of the canonical sequence.

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.

Chain 23 – 1278 NPC intracellular cholesterol transporter 1
Topological domain 23 – 261 Lumenal
Region 175 – 205 Important for cholesterol binding and cholesterol transfer from NPC1 to liposomes
Glycosylation 158 – 158 N-linked (GlcNAc...) asparagine; atypical
Glycosylation 185 – 185 N-linked (GlcNAc...) asparagine
Disulfide bond 97 – 238
Disulfide bond 177 – 184
Alternative sequence 1 – 267 Missing. In isoform 2.
Mutagenesis 25 – 257 Missing. Decreases affinity for NPC2. Abolishes cholesterol transfer from NPC2 to NPC1.
Mutagenesis 185 – 185 N -> Q. Reduces glycosylation; when associated with Q-70 and Q-122. No effect on cholesterol and 25-hydroxycholesterol binding. Strongly reduces cholesterol transfer to liposomes in a NPC2-dependent manner.
Beta strand 177 – 179

Literature citations

Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations.
Ribeiro I.; Marcao A.; Amaral O.; Sa Miranda M.C.; Vanier M.T.; Millat G.;
Hum. Genet. 109:24-32(2001)
Cited for: VARIANTS NPC1 ARG-92; TYR-177; TRP-518; CYS-942; CYS-978; ALA-1007 VAL-1035 AND THR-1061; VARIANTS ARG-215; ILE-642 AND VAL-858;

Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations.
Fernandez-Valero E.M.; Ballart A.; Iturriaga C.; Lluch M.; Macias J.; Vanier M.T.; Pineda M.; Coll M.J.;
Clin. Genet. 68:245-254(2005)
Cited for: VARIANTS NPC1 MET-137; TYR-177; TRP-372; LEU-434; LEU-474; TYR-479; ARG-576; MET-664; PHE-727; LYS-754; PRO-775; LEU-865; THR-926; CYS-942; ASN-944; HIS-948; GLU-959; 961-ASN--PHE-966 DELINS SER; ALA-1007; VAL-1035; LYS-1036; THR-1061; ASN-1066; ILE-1156; SER-1156 AND LEU-1224; VARIANTS ARG-215; ILE-642; VAL-858 AND GLN-1266;

Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families.
Millat G.; Baielo N.; Molinero S.; Rodriguez C.; Chikh K.; Vanier M.T.;
Mol. Genet. Metab. 86:220-232(2005)
Cited for: VARIANTS NPC1 SER-166; TYR-177; PRO-404; LEU-537; LEU-543; LEU-615; ARG-631; LEU-763; CYS-825; LEU-862; LEU-865; CYS-871; TYR-917; GLN-934; LEU-940; MET-950; SER-968; ALA-992; ARG-992; TRP-992; ALA-1007; MET-1036; THR-1061; VAL-1062; ASN-1097; VAL-1174; HIS-1186; VAL-1216 AND ARG-1240; VARIANT MET-511;

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.