PCSK9

protein-coding

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

Gene summary

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Previous symbols:

HCHOLA3

MANE transcript

NM_174936.4

Inheritance

AD, AR

ClinVar variants

P:34U:700B:506

Top phenotype

Hypercholesterolemia, familial, 3

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr1:55,039,445-55,064,852

External References & Databases

Ensembl (ENSG00000169174)

Transcript & Mutation Effects

hg38 • Region Span ~25.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercholesterolemia, autosomal dominant, 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011369

Submitter: ClinGen

The relationship between PCSK9 and familial hypercholesterolemia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of November 14, 2018. Variants in PCSK9 were first reported in humans with this disease as early as 2003 (Abifadel et al., PMID: 12730697). At least 15 variants (missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 17 probands in 6 publications (PMIDs: 12730697, 15772090, 22683120, 26541928, 29127338, 20006333). Variants in this gene segregated with disease in at least 31 family members. The mechanism for disease is heterozygous gain of function (Maxwell et al., 2005; PMID: 16577715), while heterozygous loss of function variants are associated with low levels of LDL cholesterol (Cohen et al., 2005, PMID: 15654334). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, PCSK9 is definitively associated with autosomal dominant familial hypercholesterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

hypercholesterolemia, autosomal dominant, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011369

Submitter: Labcorp Genetics (formerly Invitae)

hypercholesterolemia, autosomal dominant, 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011369

Submitter: Ambry Genetics

hypercholesterolemia, autosomal dominant, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011369

Submitter: Genomics England PanelApp

homozygous familial hypercholesterolemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018328

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypercholesterolemia, familial, 3AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Interventions to maintain lipid profiles at a more desirable level can decrease morbidity/mortality, such as relates to CAD

Refs: 10205269; 10764678; 12730697; 15166014; 14727156; 14727179; 15654334; 15772090; 16554528; 16909389; 18354102; 22683120

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCSK9 variants in ClinVar

13 Conditions Cataloged

Hypercholesterolemia, autosomal dominant, 3Total: 991

Familial hypercholesterolemiaTotal: 822

Cardiovascular phenotypeTotal: 529

not specifiedTotal: 229

not providedTotal: 222

Hypercholesterolemia, familial, 1Total: 108

HypobetalipoproteinemiaTotal: 58

PCSK9-related disorderTotal: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_174936.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			16 clinvar	348 clinvar	7 clinvar	371
missense	9 clinvar	21 clinvar	639 clinvar	88 clinvar	5 clinvar	762
nonsense			9 clinvar	21 clinvar		30
start loss			1 clinvar			1
frameshift	1 clinvar	1 clinvar	16 clinvar	36 clinvar		54
splice donor/acceptor (+/-2bp)		2 clinvar	19 clinvar	1 clinvar		22
Total	10	24	700	494	12	1240

Highest pathogenic variant AF is 0.00013680205

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_174936.4	RefSeq	NP_777596.2	12	MANE Select
ENST00000302118.5	Ensembl	ENSP00000303208.5	12	MANE Select
NM_001407240.1	RefSeq	NP_001394169.1	13	Standard
NM_001407241.1	RefSeq	NP_001394170.1	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pcsk9	Danio rerio	Structure: whole organism Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

pcsk9

Danio rerio

Structure: whole organism

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

kidney development
liver development
negative regulation of receptor recycling
positive regulation of receptor internalization
triglyceride metabolic process

Molecular Function

RNA binding
serine-type endopeptidase activity
protein binding
sodium channel inhibitor activity
low-density lipoprotein particle binding

Cellular Component

extracellular region
extracellular space
cytoplasm
lysosome
lysosomal membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302118
Coding exons: 12
Length: 25305
Individuals with no LoFs: 125581
Homozygous LoFs: 0
Heterozygous LoFs: 167
Defined: 125748
p: 0.000664

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.272	419	435	0.963	0.0000289	4388
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0031	0.0031	notable
Latino/Admixed American	0.00098	0.00098	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.00017	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00045	0.00043	rare
South Asian	0.00049	0.00049	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.196

Intolerance Scores

LoFtool: 0.467
RVIS EVS: 0.94
RVIS percentile EVS: 89.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.557

Gene Damage Prediction

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