NPC1L1

NPC1 like intracellular cholesterol transporter 1, the group of Solute carrier family 65, NPC-type cholesterol transporters

Basic information

Region (hg38): 7:44512535-44541330

Links

ENSG00000015520 ∙ NCBI:29881 ∙ OMIM:608010 ∙ HGNC:7898 ∙ Uniprot:Q9UHC9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ezetimibe, nonresponse to	AD/AR	Pharmacogenomic	Variants may have pharmacogenomic relevance and medication selection may be affected in patients with variants	General	15679830; 20686565

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPC1L1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPC1L1 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				11	6	17
missense			75	13	7	95
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1	1	2
non coding					2	2
Total	0	0	75	24	15

Variants in NPC1L1

This is a list of pathogenic ClinVar variants found in the NPC1L1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-44513457-C-T		not specified	Likely benign (Feb 14, 2023)
7-44513458-G-A		not specified	Uncertain significance (Oct 20, 2021)
7-44513513-A-C		not specified	Uncertain significance (Oct 06, 2021)
7-44513605-C-T		NPC1L1-related disorder	Benign (Feb 21, 2019)
7-44513634-G-A		not specified	Uncertain significance (Mar 29, 2022)
7-44513639-A-G		not specified	Benign (Mar 29, 2016)
7-44513641-C-T		not specified	Likely benign (Aug 30, 2022)
7-44513654-GGA-G		NPC1L1-related disorder	Benign (Feb 21, 2019)
7-44515806-C-T		not specified	Uncertain significance (May 21, 2024)
7-44515807-G-A		not specified	Benign (Mar 29, 2016)
7-44515822-G-A			Likely benign (Jul 01, 2022)
7-44515859-G-C		not specified	Uncertain significance (Jun 05, 2024)
7-44515869-G-C		not specified	Uncertain significance (Sep 20, 2023)
7-44515911-C-A		not specified	Uncertain significance (Feb 06, 2023)
7-44515911-C-T		not specified	Uncertain significance (Mar 26, 2024)
7-44515974-T-G		not specified	Benign (Mar 29, 2016)
7-44516085-G-T		not specified	Uncertain significance (Apr 09, 2024)
7-44516100-A-T		Ezetimibe response • not specified	Likely benign (Mar 29, 2016)
7-44516704-G-A		not specified	Uncertain significance (Jan 18, 2022)
7-44516768-T-C		not specified	Uncertain significance (Nov 14, 2023)
7-44516876-G-T		not specified	Uncertain significance (Jul 25, 2023)
7-44516910-C-G			Likely benign (May 25, 2018)
7-44517233-G-T		not specified	Uncertain significance (May 17, 2023)
7-44517235-C-A		not specified	Uncertain significance (Oct 30, 2023)
7-44517235-C-G			Benign (Jun 14, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPC1L1	protein_coding	protein_coding	ENST00000289547	20	28781

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.31e-20	0.507	125488	0	260	125748	0.00103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.409	729	761	0.958	0.0000484	8765
Missense in Polyphen		203	234.21	0.86676		2817
Synonymous	-1.44	370	336	1.10	0.0000222	2903
Loss of Function	1.94	39	54.4	0.716	0.00000309	579

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00195	0.00194
Ashkenazi Jewish	0.00	0.00
East Asian	0.00671	0.00671
Finnish	0.0000468	0.0000462
European (Non-Finnish)	0.000636	0.000633
Middle Eastern	0.00671	0.00671
South Asian	0.000393	0.000392
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down- regulates its expression and secretion by inhibiting its maturation and accelerating its degradation. {ECO:0000269|PubMed:15928087, ECO:0000269|PubMed:22095670}.
• Pathway: Fat digestion and absorption - Homo sapiens (human);Vitamin A and Carotenoid Metabolism;C21-steroid hormone biosynthesis and metabolism;Intestinal lipid absorption;Intestinal absorption;Digestion and absorption (Consensus)

Recessive Scores

• pRec: 0.187

Intolerance Scores

• loftool: 0.0150
• rvis_EVS: 1.38
• rvis_percentile_EVS: 94.54

Haploinsufficiency Scores

• pHI: 0.129
• hipred: N
• hipred_score: 0.421
• ghis: 0.471

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.319

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Npc1l1
• Phenotype: liver/biliary system phenotype; digestive/alimentary phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: cholesterol biosynthetic process;intestinal cholesterol absorption;cholesterol transport;lipoprotein metabolic process;response to drug;cellular response to sterol depletion;intestinal lipid absorption
• Cellular component: plasma membrane;apical plasma membrane;cytoplasmic vesicle membrane;brush border membrane;spanning component of plasma membrane
• Molecular function: protein binding;drug binding;Rab GTPase binding;myosin V binding