NPC1

NPC intracellular cholesterol transporter 1, the group of Solute carrier family 65, NPC-type cholesterol transporters

Basic information

Region (hg38): 18:23506183-23586506

Links

ENSG00000141458 ∙ NCBI:4864 ∙ OMIM:607623 ∙ HGNC:7897 ∙ Uniprot:O15118 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the NPC1 gene.

• Niemann-Pick disease, type C1 (1956 variants)
• not provided (423 variants)
• not specified (99 variants)
• Inborn genetic diseases (92 variants)
• Niemann-Pick disease, type C (78 variants)
• NPC1-related condition (23 variants)
• Niemann-Pick disease, type C1, juvenile form (3 variants)
• Sphingomyelin/cholesterol lipidosis (3 variants)
• Abnormality of metabolism/homeostasis (2 variants)
• Dystonic disorder (2 variants)
• See cases (2 variants)
• 6 conditions (2 variants)
• Capillary hemangioma (1 variants)
• Seizure;Intellectual disability (1 variants)
• Niemann-Pick disease, type D (1 variants)
• Niemann-Pick disease, type C1, adult form (1 variants)
• Niemann-Pick disease, type C2 (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			8	476	3	487
missense	34	112	446	10	6	608
nonsense	30	46				76
start loss		2				2
frameshift	110	72	4			186
inframe indel	1	8	10			19
splice donor/acceptor (+/-2bp)	17	41	1			59
splice region	1		39	98	6	144
non coding		2	29	326	45	402
Total	192	283	498	812	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)
18-23526674-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)
18-23532093-A-C		Niemann-Pick disease, type C1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

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: dbNSFP

• 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