PPT1
protein-codingpalmitoyl-protein thioesterase 1, the group of Depalmitoylases
Gene summary
The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]
- PPT
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0016295
Submitter: ClinGen
*PPT1* was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) (MONDO:0016295) in 1998 (Mitchison et al., PMID: 9425237). Of note, NCL is also referred to as Batten disease and, in the case of NCL caused by variants in *PPT1*, ceroid lipofuscinosis, neuronal 1 (CLN1). NCL is a lysosomal storage disorder that is often characterized by intracellular accumulation of autofluorescent lipopigments and progressive neurodegeneration beginning in childhood, and can involve a variety of phenotypes including: seizures, cognitive decline, vision deterioration, blindness, and brain atrophy. Nine variants (missense, frameshift, nonsense, and intronic) that have been reported in 12 probands in three publications are included in this curation (PMIDs: 31741823, 19793312, 19302939). Of all variants described, one nonsense variant, p.Arg151*, has been reported to account for 40% of all known alleles (PMID: 9664077). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models (PMIDs: 11717424, 31289301). In summary, there is definitive evidence supporting the relationship between *PPT1* and neuronal ceroid lipofuscinosis (MONDO:0016295). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Epilepsy GCEP on the meeting date June 16, 2020 (SOP Version 7). As of March 30, 2023, this record underwent administrative updates. Evidence scoring was modified to reflect the new recommendations made in SOP Version 9. An evidence summary was also added. No new evidence was reviewed or added at that time. Most recently, on June 10, 2024, this record underwent further administrative updates to include the ClinGen Retina GCEP as a secondary contributor. Additional explanatory text was added to the evidence summary, but the original evidence was not changed.
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009744
Submitter: Myriad Women's Health
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PPT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000310.4. 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 | 7 | 146 | 153 | |||
| missense | 9 | 42 | 174 | 2 | 2 | 229 |
| nonsense | 16 | 17 | 33 | |||
| start loss | 3 | 3 | 6 | |||
| frameshift | 27 | 31 | 58 | |||
| splice donor/acceptor (+/-2bp) | 12 | 24 | 3 | 39 | ||
| Total | 67 | 117 | 184 | 148 | 2 | 518 |
Highest pathogenic variant AF is 0.00045356588
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000301.1 | 9 | MANE Select | |
| Ensembl | ENSP00000493153.1 | 9 | MANE Select | |
| RefSeq | NP_001136076.1 | 6 | Standard | |
| RefSeq | NP_001350624.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
- Fatty acid elongation - Homo sapiens (human)
- Long-chain-3-hydroxyacyl-coa dehydrogenase deficiency (LCHAD)
- Fatty Acid Elongation In Mitochondria
- Metabolism of lipids
Biological Process
- protein depalmitoylation
- receptor-mediated endocytosis
- pinocytosis
- lysosomal lumen acidification
- neurotransmitter secretion
Molecular Function
- protein binding
- palmitoyl-(protein) hydrolase activity
- palmitoyl-CoA hydrolase activity
Cellular Component
- extracellular region
- nucleus
- lysosome
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000433473
- Coding exons
- 9
- Length
- 24997
- Individuals with no LoFs
- 125645
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 103
- Defined
- 125748
- p
- 0.000410
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0339 | 163 | 164 | 0.993 | 0.00000885 | 2006 |
| Missense (PolyPhen) | 51 | 61.262 | 0.83249 | 817 | ||
| Synonymous | -1.10 | 74 | 62.9 | 1.18 | 0.00000343 | 582 |
| Loss of Function | 1.94 | 10 | 19.2 | 0.521 | 9.90e-7 | 210 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00082 | 0.00082 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. Prefers acyl chain lengths of 14 to 18 carbons (PubMed:8816748). {ECO:0000269|PubMed:8816748}.;
- Disease
- DISEASE: Ceroid lipofuscinosis, neuronal, 1 (CLN1) [MIM:256730]: A form of neuronal ceroid lipofuscinosis with variable age at onset. Infantile, late-infantile, juvenile, and adult onset have been reported. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD). {ECO:0000269|PubMed:11506414, ECO:0000269|PubMed:19201763, ECO:0000269|PubMed:19941651, ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:7637805, ECO:0000269|PubMed:9425237, ECO:0000269|PubMed:9664077}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.583
Intolerance Scores
- LoFtool
- 0.204
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.91
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |