PLCE1
protein-codingphospholipase C epsilon 1, the group of C2 domain containing phospholipases|Phospholipases
Gene summary
This gene encodes a phospholipase enzyme that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers subsequently regulate various processes affecting cell growth, differentiation, and gene expression. This enzyme is regulated by small monomeric GTPases of the Ras and Rho families and by heterotrimeric G proteins. In addition to its phospholipase C catalytic activity, this enzyme has an N-terminal domain with guanine nucleotide exchange (GEF) activity. Mutations in this gene cause early-onset nephrotic syndrome; characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~338.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: Natera
Inheritance Pattern: AD
Disease ID:MONDO:0019006
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012546
Submitter: ClinGen
The *PLCE1* gene is located on chromosome 10 at q23.3 and encodes the phospholipase C epsilon 1 protein, which is an enzyme that regulates proliferation, migration and differentiation of podocytes. *PLCE1* was first reported in relation to autosomal recessive nephrotic syndrome type 3 in 2006 (Hinkes et al., PMID: 10997929, OMIM:610725). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - *PLCE1*’. The mechanism of pathogenicity is known to be loss of function. Nephrotic syndrome - *PLCE1* is characterized by significant protein loss in the urine within the first months of life causing generalized edema. At least 46 variants (frameshift, nonsense, splice, missense) have been reported in 56 probands in 6 publications (PMIDs: 10997929, 35034193, 29127259, 25349199, 18709391, 18065803 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 25521631, 32238860, 32223311, 17942568, 10997929). PLCE1 knockout human podocytes showed reduced markers of podocytes including NPHS1, NEPH1, WT1, and SYPO (PMID: 32238860) in addition to reduced podocyte proliferation. Also, podocytes transfected with PLCE1 siRNA exhibited a significant decrease in Rac1 and Cdc42 levels that regulate podocyte actin cytoskeleton stabilization (PMID: 32238860). In particular, PLCE1 knockdown zebrafish showed signs of podocytopathy (PMID: 10997929). Interestingly, PLCE1 knockout mice exhibited normal kidney structure and function (PMIDs: 32223311, 10997929), however, a second hit such as hypertension (Angiotensin II treatment) or nephron loss (unilateral nephrectomy) caused the development of FSGS lesions (PMID: 32223311). A total of 5.5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *PLCE1* and autosomal recessive nephrotic syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Renal
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
Comments: Most described individuals have had steroid-resistant disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PLCE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016341.4. 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 | 29 | 132 | 2 | 163 | ||
| missense | 1 | 3 | 516 | 52 | 4 | 576 |
| nonsense | 19 | 8 | 1 | 28 | ||
| start loss | 0 | |||||
| frameshift | 15 | 19 | 2 | 36 | ||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 2 | 8 | ||
| Total | 36 | 35 | 550 | 184 | 6 | 811 |
Highest pathogenic variant AF is 0.0000588742
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057425.3 | 31 | MANE Select | |
| Ensembl | ENSP00000360431.2 | 31 | MANE Select | |
| RefSeq | NP_001159451.1 | 31 | Standard | |
| RefSeq | NP_001275918.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| plce1 | Danio rerio | Structure: pronephric glomerular basement membrane Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inositol phosphate metabolism - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
- Thyroid hormone signaling pathway - Homo sapiens (human)
- Calcium signaling pathway - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
Biological Process
- activation of MAPK activity
- regulation of cell growth
- diacylglycerol biosynthetic process
- regulation of smooth muscle contraction
- cytoskeleton organization
Molecular Function
- phosphatidylinositol phospholipase C activity
- phospholipase C activity
- guanyl-nucleotide exchange factor activity
- protein binding
- Ras GTPase binding
Cellular Component
- Golgi membrane
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371380
- Coding exons
- 31
- Length
- 338835
- Individuals with no LoFs
- 124708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 107
- Defined
- 124815
- p
- 0.000429
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.38 | 1061 | 1.20e+3 | 0.888 | 0.0000663 | 15223 |
| Missense (PolyPhen) | 349 | 481.35 | 0.72504 | 6118 | ||
| Synonymous | 0.613 | 443 | 460 | 0.964 | 0.0000279 | 4348 |
| Loss of Function | 6.30 | 39 | 110 | 0.353 | 0.00000684 | 1310 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00026 | rare |
| Latino/Admixed American | 0.00075 | 0.00075 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000093 | 0.000093 | rare |
| European (Non-Finnish) | 0.00035 | 0.00034 | rare |
| South Asian | 0.0011 | 0.00075 | notable |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. PLCE1 is a bifunctional enzyme which also regulates small GTPases of the Ras superfamily through its Ras guanine- exchange factor (RasGEF) activity. As an effector of heterotrimeric and small G-protein, it may play a role in cell survival, cell growth, actin organization and T-cell activation. {ECO:0000269|PubMed:11022047, ECO:0000269|PubMed:11395506, ECO:0000269|PubMed:11715024, ECO:0000269|PubMed:11877431, ECO:0000269|PubMed:12721365, ECO:0000269|PubMed:16537651, ECO:0000269|PubMed:17086182}.;
- Disease
- DISEASE: Nephrotic syndrome 3 (NPHS3) [MIM:610725]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS3 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. {ECO:0000269|PubMed:17086182}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.116
Intolerance Scores
- LoFtool
- 0.802
- RVIS EVS
- 0.36
- RVIS percentile EVS
- 74.59
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.398
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |