GPC3
protein-codingglypican 3, the group of Glypicans
Gene summary
Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
- SDYS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~451.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0020602
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0020602
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0020602
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010731
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0020602
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010731
Submitter: ClinGen
*GPC3* was first reported in relation to X-linked Simpson-Golabi-Behmel syndrome in 1996 (Pilia et al., PMID: 8589713). Simpson-Golabi-Behmel syndrome is characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, mild to severe intellectual disability with or without structural brain anomalies, and other congenital abnormalities. While normal intelligence has been reported, 47% of the Simpson-Golabi-Behmel patients with *GPC3* variants have intellectual disability (Cottereau et al., PMID: 23606591). Carrier females may have mild manifestations due to skewed X-inactivation. More than 27 unique pathogenic variants in *GPC3* have been reported in ClinVar. An overview of 86 distinct *GPC3* variants showed that the vast majority are deletions or truncating mutations (Vuillaume et al., PMID: 29637653). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function (Vuillaume et al., PMID: 29637653). This gene-disease relationship is also supported by animal models. It is noteworthy that Simpson-Golabi-Behmel syndrome can also be caused by variants in *OFD1* (see OMIM). In summary, there is definitive evidence supporting the relationship between *GPC3* and X-linked Simpson-Golabi-Behmel syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 31, 2019 (SOP Version 6).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Oncologic
Rationale: The disorder, which can include certain types of tumors, should be clinically recognizable, but surveillance for neoplasms may allow early diagnosis and treatment, which may ameliorate morbidity and mortality; Awareness of the risk of cardiac sequelae, which can include anatomic anomalies and dysrhythmias, may allow prompt detection and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GPC3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004484.4. 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 | 248 | 14 | 278 | ||
| missense | 2 | 4 | 483 | 77 | 7 | 573 |
| nonsense | 18 | 5 | 6 | 29 | ||
| start loss | 1 | 1 | ||||
| frameshift | 19 | 14 | 1 | 34 | ||
| splice donor/acceptor (+/-2bp) | 5 | 7 | 11 | 23 | ||
| Total | 44 | 30 | 518 | 325 | 21 | 938 |
Highest pathogenic variant AF is 0.000008903134
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004475.1 | 8 | MANE Select | |
| Ensembl | ENSP00000359854.3 | 8 | MANE Select | |
| RefSeq | NP_001158089.1 | 9 | Standard | |
| RefSeq | NP_001158090.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Proteoglycans in cancer - Homo sapiens (human)
- WNT-Ncore
- HH-Ncore
- Signaling by GPCR
- Signal Transduction
Biological Process
- retinoid metabolic process
- branching involved in ureteric bud morphogenesis
- glycosaminoglycan biosynthetic process
- glycosaminoglycan catabolic process
- response to bacterium
Molecular Function
- protein binding
- peptidyl-dipeptidase inhibitor activity
Cellular Component
- endoplasmic reticulum lumen
- Golgi lumen
- plasma membrane
- intrinsic component of plasma membrane
- lysosomal lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394299
- Coding exons
- 9
- Length
- 450150
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.45 | 161 | 222 | 0.726 | 0.0000161 | 4011 |
| Missense (PolyPhen) | 23 | 50.406 | 0.45629 | 948 | ||
| Synonymous | 0.0378 | 87 | 87.5 | 0.995 | 0.00000676 | 1121 |
| Loss of Function | 3.98 | 0 | 18.4 | 0.00 | 0.00000148 | 321 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cell surface proteoglycan that bears heparan sulfate (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity). {ECO:0000250|UniProtKB:Q6V9Y8, ECO:0000250|UniProtKB:Q8CFZ4, ECO:0000269|PubMed:14610063, ECO:0000269|PubMed:16227623, ECO:0000269|PubMed:17549790, ECO:0000269|PubMed:24496449}.;
- Disease
- DISEASE: Simpson-Golabi-Behmel syndrome 1 (SGBS1) [MIM:312870]: A condition characterized by pre- and postnatal overgrowth (gigantism), facial dysmorphism and a variety of inconstant visceral and skeletal malformations. Characteristic dysmorphic features include macrocephaly with coarse, distinctive facies with a large protruding jaw, broad nasal bridge and cleft palate. Cardiac defects are frequent. {ECO:0000269|PubMed:10814714}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.362
Intolerance Scores
- RVIS EVS
- -0.45
- RVIS percentile EVS
- 24.19
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.893
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |