NPC1
NPC intracellular cholesterol transporter 1, the group of Solute carrier family 65, NPC-type cholesterol transporters
Basic information
Region (hg38): 18:23506184-23586506
Links
Phenotypes
GenCC
Source:
- Niemann-Pick disease, type C1 (Definitive), mode of inheritance: AR
- Niemann-Pick disease, type C1 (Definitive), mode of inheritance: AR
- Niemann-Pick disease, type C1 (Strong), mode of inheritance: AR
- Niemann-Pick disease, type C1 (Strong), mode of inheritance: AR
- Niemann-Pick disease type C, severe perinatal form (Supportive), mode of inheritance: AR
- Niemann-Pick disease type C, severe early infantile neurologic onset (Supportive), mode of inheritance: AR
- Niemann-Pick disease type C, late infantile neurologic onset (Supportive), mode of inheritance: AR
- Niemann-Pick disease type C, juvenile neurologic onset (Supportive), mode of inheritance: AR
- Niemann-Pick disease type C, adult neurologic onset (Supportive), mode of inheritance: AR
- Niemann-Pick disease, type C1 (Definitive), mode of inheritance: AR
- Niemann-Pick disease, type C1 (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Niemann-Pick disease, type C1; Niemann-Pick disease, type D | AR | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Biochemical; Gastrointestinal; Neurologic; Ophthalmologic | 3865225; 3378364; 9211849; 9245994; 9634529; 9512307; 10361985; 10480349; 11182931; 12555942; 12408188; 15596783; 12955717; 15465421; 15465428; 16098014; 17497724; 17689147; 20301473; 19206179; 20484681; 32033912 |
ClinVar
This is a list of variants' phenotypes submitted to
- Niemann-Pick disease, type C1 (210 variants)
- not provided (26 variants)
- Niemann-Pick disease, type C (17 variants)
- NPC1-related disorder (3 variants)
- Inborn genetic diseases (3 variants)
- Niemann-Pick disease, type C1, juvenile form (2 variants)
- 6 conditions (1 variants)
- Niemann-Pick disease, type C2 (1 variants)
- Sphingomyelin/cholesterol lipidosis (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPC1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 547 | 557 | ||||
| missense | 36 | 127 | 452 | 10 | 632 | |
| nonsense | 34 | 48 | 82 | |||
| start loss | 2 | |||||
| frameshift | 127 | 71 | 202 | |||
| inframe indel | 19 | |||||
| splice donor/acceptor (+/-2bp) | 18 | 46 | 65 | |||
| splice region | 1 | 35 | 108 | 6 | 150 | |
| non coding | 26 | 451 | 44 | 524 | ||
| Total | 217 | 305 | 499 | 1008 | 54 |
Highest pathogenic variant AF is 0.000223
Variants in NPC1
This is a list of pathogenic ClinVar variants found in the NPC1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 18-23515960-G-A | Benign (Jul 15, 2018) | |||
| 18-23515989-A-G | not specified | Uncertain significance (Sep 17, 2021) | ||
| 18-23516323-G-T | not specified | Uncertain significance (Aug 10, 2021) | ||
| 18-23516432-G-A | Likely benign (Jul 15, 2018) | |||
| 18-23518925-A-G | not specified | Uncertain significance (Jul 20, 2021) | ||
| 18-23524186-T-A | not specified | Likely benign (May 10, 2024) | ||
| 18-23526674-A-C | Benign (Apr 09, 2018) | |||
| 18-23527835-C-G | Benign (Jun 13, 2018) | |||
| 18-23527897-C-T | not specified | Uncertain significance (Sep 01, 2021) | ||
| 18-23529669-T-C | not specified | Uncertain significance (Nov 08, 2021) | ||
| 18-23530033-C-T | Benign (Mar 29, 2018) | |||
| 18-23531484-G-A | Niemann-Pick disease, type C1 | Uncertain significance (Jan 12, 2018) | ||
| 18-23531702-T-C | Niemann-Pick disease, type C1 | Uncertain significance (Jan 12, 2018) | ||
| 18-23531708-C-A | Niemann-Pick disease, type C1 | Uncertain significance (Jan 13, 2018) | ||
| 18-23531716-G-GT | Niemann-Pick disease, type C | Uncertain significance (Jun 14, 2016) | ||
| 18-23531853-C-T | Niemann-Pick disease, type C | Uncertain significance (Jun 14, 2016) | ||
| 18-23531868-A-T | Niemann-Pick disease, type C1 | Uncertain significance (Jan 12, 2018) | ||
| 18-23531874-T-G | Niemann-Pick disease, type C1 | Uncertain significance (Jan 13, 2018) | ||
| 18-23531875-G-A | Niemann-Pick disease, type C1 | Uncertain significance (Mar 16, 2018) | ||
| 18-23531886-CCTTTACA-C | Niemann-Pick disease, type C | Conflicting classifications of pathogenicity (Jul 01, 2023) | ||
| 18-23532000-G-A | Niemann-Pick disease, type C1 | Uncertain significance (Jan 12, 2018) | ||
| 18-23532011-G-T | Niemann-Pick disease, type C1 | Uncertain significance (Jan 12, 2018) | ||
| 18-23532038-A-G | Niemann-Pick disease, type C1 | Benign/Likely benign (Jul 14, 2018) | ||
| 18-23532041-G-A | Niemann-Pick disease, type C1 | Uncertain significance (Jan 13, 2018) | ||
| 18-23532073-A-C | Niemann-Pick disease, type C1 | Uncertain significance (Jan 13, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NPC1 | protein_coding | protein_coding | ENST00000269228 | 25 | 80715 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.00000654 | 1.00 | 125655 | 0 | 93 | 125748 | 0.000370 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.09 | 637 | 719 | 0.885 | 0.0000435 | 8401 |
| Missense in Polyphen | 166 | 238.13 | 0.6971 | 2755 | ||
| Synonymous | -1.07 | 314 | 291 | 1.08 | 0.0000201 | 2503 |
| Loss of Function | 4.84 | 21 | 62.2 | 0.337 | 0.00000332 | 715 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000511 | 0.000510 |
| Ashkenazi Jewish | 0.000794 | 0.000794 |
| East Asian | 0.000273 | 0.000272 |
| Finnish | 0.000559 | 0.000554 |
| European (Non-Finnish) | 0.000405 | 0.000404 |
| Middle Eastern | 0.000273 | 0.000272 |
| South Asian | 0.000294 | 0.000294 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment (PubMed:9211849, PubMed:9927649, PubMed:10821832, PubMed:18772377, PubMed:27238017, PubMed:12554680). Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol- binding pocket in the N-terminal domain of NPC1 (PubMed:9211849, PubMed:9927649, PubMed:18772377, PubMed:19563754, PubMed:27238017, PubMed:28784760). Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket (PubMed:19563754). Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals (Probable). {ECO:0000269|PubMed:10821832, ECO:0000269|PubMed:12554680, ECO:0000269|PubMed:18772377, ECO:0000269|PubMed:19563754, ECO:0000269|PubMed:27238017, ECO:0000269|PubMed:28784760, ECO:0000269|PubMed:9211849, ECO:0000269|PubMed:9927649, ECO:0000305}.;
- Disease
- 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.;
- Pathway
- Lysosome - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);Irinotecan Pathway;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;LDL clearance;Plasma lipoprotein clearance;Transport of small molecules;C21-steroid hormone biosynthesis and metabolism;Plasma lipoprotein assembly, remodeling, and clearance
(Consensus)
Recessive Scores
- pRec
- 0.230
Intolerance Scores
- loftool
- 0.0695
- rvis_EVS
- -0.05
- rvis_percentile_EVS
- 50.02
Haploinsufficiency Scores
- pHI
- 0.197
- hipred
- Y
- hipred_score
- 0.554
- ghis
- 0.445
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.623
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |
Mouse Genome Informatics
- Gene name
- Npc1
- Phenotype
- reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); taste/olfaction phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype;
Zebrafish Information Network
- Gene name
- npc1
- Affected structure
- nucleate erythrocyte
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- protein glycosylation;endocytosis;autophagy;lysosomal transport;adult walking behavior;cholesterol metabolic process;bile acid metabolic process;negative regulation of macroautophagy;cholesterol transport;membrane raft organization;intracellular cholesterol transport;cholesterol efflux;low-density lipoprotein particle clearance;response to drug;cholesterol homeostasis;response to cadmium ion;viral entry into host cell;negative regulation of cell death;cellular response to steroid hormone stimulus;cellular response to low-density lipoprotein particle stimulus;establishment of protein localization to membrane
- Cellular component
- extracellular region;nuclear envelope;lysosome;lysosomal membrane;endoplasmic reticulum;Golgi apparatus;integral component of plasma membrane;membrane;integral component of membrane;late endosome membrane;membrane raft;perinuclear region of cytoplasm;extracellular exosome;integral component of lysosomal membrane
- Molecular function
- virus receptor activity;transmembrane signaling receptor activity;protein binding;sterol transporter activity;cholesterol binding;signaling receptor activity