PCSK1

protein-coding

proprotein convertase subtilisin/kexin type 1, 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 initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene [provided by RefSeq, Jan 2014]

Previous symbols:

NEC1

MANE transcript

NM_000439.5

Inheritance

AR, AD

ClinVar variants

P:53U:259B:133

Top phenotype

Proprotein convertase 1/3 deficiency

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr5:96,390,333-96,434,143

External References & Databases

Ensembl (ENSG00000175426)

Transcript & Mutation Effects

hg38 • Region Span ~43.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

obesity due to prohormone convertase I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010961

Submitter: Orphanet

obesity due to prohormone convertase I deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010961

Submitter: Ambry Genetics

obesity due to prohormone convertase I deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010961

Submitter: Labcorp Genetics (formerly Invitae)

obesity due to prohormone convertase I deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010961

Submitter: Genomics England PanelApp

obesity due to prohormone convertase I deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010961

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Proprotein convertase 1/3 deficiencyAD

Manifestation: Endocrine; Gastrointestinal

Intervention: Endocrine; Gastrointestinal

Rationale: Presentations may be diverse, and interventions such as early parenteral nutrition may be necessary; Endocrinologic interventions can allow induction of secondary sex characteristic and reproduction; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Comments: Endocrinologic interventions can allow induction of secondary sex characteristic and reproduction

Refs: 7477119; 9207799; 14617756; 17595246; 35528826

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCSK1 variants in ClinVar

9 Conditions Cataloged

PCSK1-related disorderTotal: 350

not providedTotal: 155

Inborn genetic diseasesTotal: 64

Obesity due to prohormone convertase I deficiencyTotal: 63

not specifiedTotal: 26

Body mass index quantitative trait locus 12Total: 9

Early onset severe obesityTotal: 5

ObesityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000439.5. 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			6 clinvar	120 clinvar	1 clinvar	127
missense	3 clinvar	18 clinvar	247 clinvar	11 clinvar	1 clinvar	280
nonsense	5 clinvar	10 clinvar	2 clinvar			17
start loss		1 clinvar				1
frameshift	4 clinvar	7 clinvar				11
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	4 clinvar			9
Total	13	40	259	131	2	445

Highest pathogenic variant AF is 0.00007819229

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000439.5	RefSeq	NP_000430.3	14	MANE Select
ENST00000311106.8	Ensembl	ENSP00000308024.2	14	MANE Select
NM_001177875.2	RefSeq	NP_001171346.1	14	Standard
ENST00000508626.5	Ensembl	ENSP00000421600.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prader-Willi and Angelman Syndrome
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
Incretin synthesis, secretion, and inactivation
Peptide hormone metabolism
Synthesis, secretion, and deacylation of Ghrelin

Biological Process

proteolysis
cell-cell signaling
protein processing
peptide hormone processing
peptide biosynthetic process

Molecular Function

serine-type endopeptidase activity
identical protein binding

Cellular Component

extracellular space
membrane
transport vesicle
secretory granule lumen
neuron projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311106
Coding exons: 14
Length: 43729
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.47	328	412	0.796	0.0000226	4964
Missense (PolyPhen)		111	185.64	0.59793		2160
Synonymous	-0.506	165	157	1.05	0.00000959	1432
Loss of Function	2.94	21	41.4	0.507	0.00000226	451

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP. {ECO:0000250|UniProtKB:P63239}.;
Disease: DISEASE: Proprotein convertase 1 deficiency (PC1 deficiency) [MIM:600955]: Characterized by obesity, hypogonadism, hypoadrenalism, reactive hypoglycemia as well as marked small- intestinal absorptive dysfunction It is due to impaired processing of prohormones. {ECO:0000269|PubMed:14617756, ECO:0000269|PubMed:17595246, ECO:0000269|PubMed:9207799}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.340

Intolerance Scores

LoFtool: 0.271
RVIS EVS: -0.42
RVIS percentile EVS: 25.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.808

Gene Damage Prediction

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