GeneBe

CTSC

protein-coding

cathepsin C, the group of Cathepsins

Gene summary

This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. [provided by RefSeq, Nov 2015]

Previous symbols:
  • PLS
  • PALS

MANE transcript

NM_001814.6

Inheritance

AR

ClinVar variants

P:95U:178B:149

Top phenotype

Haim-Munk syndrome; Papillon-Lefevre syndrome; Periodontitis 1, juvenile

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr11:88,265,069-88,359,684

External References & Databases

Ensembl (ENSG00000109861)NCBI Gene (1075)OMIM (602365)HGNC:2528GenCCUniProt (P53634)AlphaFoldClinVar (CTSC)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~94.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Haim-Munk syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009491

Submitter: Labcorp Genetics (formerly Invitae)

Haim-Munk syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009491

Submitter: Labcorp Genetics (formerly Invitae)

Papillon-Lefevre diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009490

Submitter: Ambry Genetics

Papillon-Lefevre diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009490

Submitter: Orphanet

periodontitis, aggressive 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008226

Submitter: Labcorp Genetics (formerly Invitae)

ectodermal dysplasia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019287

Submitter: Illumina

Haim-Munk syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009491

Submitter: Ambry Genetics

Haim-Munk syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009491

Submitter: G2P

Haim-Munk syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009491

Submitter: Orphanet

Papillon-Lefevre diseaseLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0009490

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Haim-Munk syndrome; Papillon-Lefevre syndrome; Periodontitis 1, juvenileAR

Manifestation: Allergy/Immunology/Infectious; Dental; Dermatologic; Musculoskeletal

Intervention: Allergy/Immunology/Infectious

Rationale: Early diagnosis to allow control of oral infections may preserve dentition

Refs: 14244097; 14252683; 162525; 2943312; 2965550; 7623262; 9085215; 10593994; 10581027; 11106356; 10662807; 12509601; 12637913; 14974080; 15606524; 18945301; 19816003; 20359428; 21393975Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTSC variants in ClinVar

9 Conditions Cataloged
Papillon-Lefèvre syndromeTotal: 437
Haim-Munk syndromeTotal: 423
Periodontitis, aggressiveTotal: 417
Inborn genetic diseasesTotal: 53
not specifiedTotal: 42
not providedTotal: 27
CTSC-related disorderTotal: 20
Periodontitis, aggressive 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001814.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
141
clinvar
 143
missense
7
clinvar
18
clinvar
166
clinvar
8
clinvar
 199
nonsense
24
clinvar
4
clinvar
1
clinvar
 29
start loss
1
clinvar
 1
frameshift
27
clinvar
2
clinvar
3
clinvar
 32
splice donor/acceptor (+/-2bp)
5
clinvar
7
clinvar
6
clinvar
 18
Total63321781490422

Highest pathogenic variant AF is 0.000045853936

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001814.6RefSeqNP_001805.47MANE Select
ENST00000227266.10EnsemblENSP00000227266.47MANE Select
NM_001114173.3RefSeqNP_001107645.14Standard
NM_148170.5RefSeqNP_680475.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Apoptosis - Homo sapiens (human)
  • miR-targeted genes in epithelium - TarBase
  • miR-targeted genes in leukocytes - TarBase
  • miR-targeted genes in lymphocytes - TarBase

Biological Process

  • T cell mediated cytotoxicity
  • proteolysis
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • apoptotic process
  • immune response

Molecular Function

  • cysteine-type endopeptidase activity
  • serine-type endopeptidase activity
  • protein binding
  • cysteine-type peptidase activity
  • peptidase activator activity involved in apoptotic process

Cellular Component

  • Golgi membrane
  • extracellular region
  • extracellular space
  • nucleoplasm
  • lysosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000227266
Coding exons
7
Length
44196
Individuals with no LoFs
125704
Homozygous LoFs
0
Heterozygous LoFs
44
Defined
125748
p
0.000175
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1432522461.030.00001233026
Missense (PolyPhen)9283.9271.09621097
Synonymous-0.90910593.81.120.00000469889
Loss of Function1.441421.10.6620.00000104246

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000690.000062rare
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish0.000220.00018rare
European (Non-Finnish)0.000210.00020rare
South Asian0.000200.00016rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII. {ECO:0000269|PubMed:1586157}.;
Disease
DISEASE: Papillon-Lefevre syndrome (PLS) [MIM:245000]: An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. {ECO:0000269|PubMed:10581027, ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:11106356, ECO:0000269|PubMed:11158173, ECO:0000269|PubMed:11180012, ECO:0000269|PubMed:11180601, ECO:0000269|PubMed:11886537, ECO:0000269|PubMed:12112662, ECO:0000269|PubMed:12809647, ECO:0000269|PubMed:14974080, ECO:0000269|PubMed:15108292, ECO:0000269|PubMed:15991336, ECO:0000269|PubMed:25799584}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Haim-Munk syndrome (HMS) [MIM:245010]: An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. {ECO:0000269|PubMed:10662807}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodontititis, aggressive, 1 (AP1) [MIM:170650]: A disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. {ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:14974080}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.665

Intolerance Scores

LoFtool
0.165
RVIS EVS
-0.45
RVIS percentile EVS
24.33

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.277

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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