PCSK9

proprotein convertase subtilisin/kexin type 9, the group of Proprotein convertase subtilisin/kexin family

Basic information

Region (hg38): 1:55039446-55064852

Previous symbols: [ "HCHOLA3" ]

Links

ENSG00000169174 ∙ NCBI:255738 ∙ OMIM:607786 ∙ HGNC:20001 ∙ Uniprot:Q8NBP7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypercholesterolemia, autosomal dominant, 3 (Strong), mode of inheritance: AD
• homozygous familial hypercholesterolemia (Supportive), mode of inheritance: AR
• hypercholesterolemia, autosomal dominant, 3 (Strong), mode of inheritance: AD
• hypercholesterolemia, autosomal dominant, 3 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypercholesterolemia, familial, 3	AD	Cardiovascular	Interventions to maintain lipid profiles at a more desirable level can decrease morbidity/mortality, such as relates to CAD	Cardiovascular	10205269; 10764678; 12730697; 15166014; 14727156; 14727179; 15654334; 15772090; 16554528; 16909389; 18354102; 22683120

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PCSK9 gene.

• Familial hypercholesterolemia (629 variants)
• Hypercholesterolemia, autosomal dominant, 3 (523 variants)
• Cardiovascular phenotype (301 variants)
• Hypercholesterolemia, familial, 1 (167 variants)
• not provided (132 variants)
• not specified (131 variants)
• Hypobetalipoproteinemia (102 variants)
• Familial hypobetalipoproteinemia (32 variants)
• Inborn genetic diseases (9 variants)
• PCSK9-related condition (7 variants)
• Hypocholesterolemia (4 variants)
• Short fetal femur length (3 variants)
• PCSK9-Related Disorders (3 variants)
• Low density lipoprotein cholesterol level quantitative trait locus 1 (3 variants)
• High myopia (2 variants)
• Homozygous familial hypercholesterolemia (1 variants)
• Hypercholesterolemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PCSK9 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			7	236	1	244
missense	2	9	372	21	1	405
nonsense			4	11		15
start loss			1			1
frameshift	1		8	17		26
inframe indel			6	7		13
splice donor/acceptor (+/-2bp)			11	1		12
splice region			17	28	3	48
non coding			66	62	27	155
Total	3	9	475	355	29

Highest pathogenic variant AF is 0.00000657

Variants in PCSK9

This is a list of pathogenic ClinVar variants found in the PCSK9 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-55039485-G-T		Hypercholesterolemia, familial, 1 • Familial hypobetalipoproteinemia	Uncertain significance (Jun 14, 2016)
1-55039492-G-C		Hypercholesterolemia, autosomal dominant, 3 • Hypobetalipoproteinemia	Uncertain significance (Jan 12, 2018)
1-55039507-C-A		Hypercholesterolemia, familial, 1 • Hypobetalipoproteinemia • Hypercholesterolemia, autosomal dominant, 3 • not specified	Uncertain significance (Mar 08, 2024)
1-55039530-A-G		Familial hypercholesterolemia	Uncertain significance (May 17, 2023)
1-55039551-G-A		Hypercholesterolemia, familial, 1 • Hypobetalipoproteinemia • Hypercholesterolemia, autosomal dominant, 3	Benign/Likely benign (Jan 12, 2018)
1-55039593-G-C		Hypercholesterolemia, autosomal dominant, 3 • Hypobetalipoproteinemia	Uncertain significance (Aug 19, 2021)
1-55039593-G-T		Hypercholesterolemia, familial, 1 • Hypobetalipoproteinemia • Hypercholesterolemia, autosomal dominant, 3	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-55039601-T-G		Familial hypobetalipoproteinemia • Hypercholesterolemia, familial, 1	Uncertain significance (Jun 14, 2016)
1-55039617-T-G		Hypercholesterolemia, familial, 1 • Familial hypobetalipoproteinemia	Uncertain significance (Jun 14, 2016)
1-55039638-C-A		Hypercholesterolemia, familial, 1 • Familial hypobetalipoproteinemia	Uncertain significance (Jun 14, 2016)
1-55039653-A-G		Hypercholesterolemia, familial, 1 • Familial hypobetalipoproteinemia	Uncertain significance (Jun 14, 2016)
1-55039658-T-G		Familial hypobetalipoproteinemia • Hypercholesterolemia, familial, 1	Uncertain significance (Jun 14, 2016)
1-55039670-C-A		Hypercholesterolemia, familial, 1	Benign (-)
1-55039698-C-T		Hypobetalipoproteinemia • Hypercholesterolemia, autosomal dominant, 3	Conflicting classifications of pathogenicity (Apr 28, 2017)
1-55039765-A-G		Hypercholesterolemia, familial, 1	Uncertain significance (Mar 01, 2016)
1-55039770-C-T		Hypercholesterolemia, autosomal dominant, 3 • Hypobetalipoproteinemia	Uncertain significance (Jan 12, 2018)
1-55039771-C-A		Hypercholesterolemia, familial, 1	Uncertain significance (Mar 01, 2016)
1-55039774-C-T		Hypercholesterolemia, familial, 1 • Hypobetalipoproteinemia • Hypercholesterolemia, autosomal dominant, 3	Benign (Jan 13, 2018)
1-55039812-G-A		Hypercholesterolemia, autosomal dominant, 3 • Hypobetalipoproteinemia	Benign/Likely benign (Jan 13, 2018)
1-55039828-C-T		Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (May 04, 2023)
1-55039829-C-T		Familial hypercholesterolemia	Likely benign (Mar 12, 2018)
1-55039829-CT-C		Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (Apr 10, 2023)
1-55039830-T-C		Hypercholesterolemia, familial, 1 • Familial hypercholesterolemia • PCSK9-related disorder • Hypercholesterolemia, autosomal dominant, 3	Conflicting classifications of pathogenicity (Feb 05, 2024)
1-55039831-G-A		Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (Nov 20, 2023)
1-55039834-C-A		Hypercholesterolemia, autosomal dominant, 3	Uncertain significance (Dec 13, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PCSK9	protein_coding	protein_coding	ENST00000302118	12	25305

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.71e-17	0.00860	125581	0	167	125748	0.000664

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.272	419	435	0.963	0.0000289	4388
Missense in Polyphen		126	132.2	0.9531		1432
Synonymous	1.01	170	188	0.907	0.0000128	1465
Loss of Function	0.162	26	26.9	0.966	0.00000127	285

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00408	0.00406
Ashkenazi Jewish	0.00130	0.00129
East Asian	0.000166	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000452	0.000431
Middle Eastern	0.000166	0.000163
South Asian	0.000491	0.000490
Other	0.000335	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments (PubMed:18039658). Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:18799458, PubMed:17461796, PubMed:18197702, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non- acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)- mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22074827, ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899}.
• Disease: DISEASE: Hypercholesterolemia, autosomal dominant, 3 (HCHOLA3) [MIM:603776]: A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins. {ECO:0000269|PubMed:12730697, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:24808179}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cholesterol metabolism - Homo sapiens (human);Proprotein convertase subtilisin-kexin type 9 (PCSK9) mediated LDL receptor degradation;Evolocumab Mechanism;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;LDL clearance;VLDLR internalisation and degradation;Plasma lipoprotein clearance;Transport of small molecules;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Plasma lipoprotein assembly, remodeling, and clearance (Consensus)

Recessive Scores

• pRec: 0.196

Intolerance Scores

• loftool: 0.467
• rvis_EVS: 0.94
• rvis_percentile_EVS: 89.89

Haploinsufficiency Scores

• pHI: 0.342
• hipred: N
• hipred_score: 0.318
• ghis: 0.374

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.557

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pcsk9
• Phenotype: liver/biliary system phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: pcsk9
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: dead

Gene ontology

• Biological process: kidney development;liver development;negative regulation of receptor recycling;positive regulation of receptor internalization;triglyceride metabolic process;phospholipid metabolic process;apoptotic process;lysosomal transport;cholesterol metabolic process;cellular response to starvation;regulation of signaling receptor activity;negative regulation of low-density lipoprotein particle clearance;protein autoprocessing;neurogenesis;neuron differentiation;low-density lipoprotein particle receptor catabolic process;positive regulation of low-density lipoprotein particle receptor catabolic process;cellular response to insulin stimulus;low-density lipoprotein particle clearance;lipoprotein metabolic process;cholesterol homeostasis;regulation of neuron apoptotic process;positive regulation of neuron apoptotic process;post-translational protein modification;cellular protein metabolic process;negative regulation of low-density lipoprotein particle receptor binding;negative regulation of low-density lipoprotein receptor activity;negative regulation of receptor-mediated endocytosis involved in cholesterol transport;negative regulation of signaling receptor activity;negative regulation of sodium ion transmembrane transporter activity
• Cellular component: extracellular region;extracellular space;cytoplasm;lysosome;lysosomal membrane;early endosome;late endosome;endoplasmic reticulum;endoplasmic reticulum lumen;rough endoplasmic reticulum;Golgi apparatus;plasma membrane;cell surface;COPII-coated ER to Golgi transport vesicle;extrinsic component of external side of plasma membrane;endolysosome membrane;perinuclear region of cytoplasm;PCSK9-LDLR complex;PCSK9-AnxA2 complex
• Molecular function: RNA binding;serine-type endopeptidase activity;protein binding;sodium channel inhibitor activity;low-density lipoprotein particle binding;receptor inhibitor activity;apolipoprotein binding;very-low-density lipoprotein particle binding;apolipoprotein receptor binding;protein self-association;low-density lipoprotein particle receptor binding;very-low-density lipoprotein particle receptor binding