GP6
protein-codingglycoprotein VI platelet, the group of Ig-like cell adhesion molecule family|Immunoglobulin like domain containing
Gene summary
This gene encodes a platelet membrane glycoprotein of the immunoglobulin superfamily. The encoded protein is a receptor for collagen and plays a critical role in collagen-induced platelet aggregation and thrombus formation. The encoded protein forms a complex with the Fc receptor gamma-chain that initiates the platelet activation signaling cascade upon collagen binding. Mutations in this gene are a cause of platelet-type bleeding disorder-11 (BDPLT11). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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:0013623
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013623
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013623
Submitter: ClinGen
The relationship between GP6 and Platelet-type bleeding disorder 11, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October 9, 2019. GP6 encodes the platelet membrane glycoprotein receptor for collagen. GPVI plays a critical role in collagen-induced platelet aggregation (PMID: 31351674, 31068042). Platelet-type bleeding disorder 11 is characterized by mild bleeding phenotypes and absent platelet aggregation in response to collagen (PMID: 31351674, 31068042). GP6 was first reported in relation to autosomal recessive Platelet-type bleeding disorder 11 in 2009 (Hermans et al, 2009; PMID: 19552682 and Dumont et al, 2009; PMID: 19549989). At least 5 missense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (9.5 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 19552682, 19549989, 23815599). The mechanism for disease is biallelic loss of function. Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models and expression studies. GP6-knock-out mice show absent platelet aggregation in response to collagen, similar to human patients (PMIDs: 12738669, 16139873) and platelets from GPVI-deficient mice are functionally abnormal (PMID: 12515812). The expression of GP6 is restricted to platelets and megakaryocytes (PMID: 10961879, 11278467). In summary, the GP6 - Platelet-type Bleeding Disorder 11 gene-disease relationship is definitive. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October 23, 2019 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0013623
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals may demonstrate a bleeding diathesis (including postraumatic/postsurgical), and surveillance and prompt treatment of bleeding episodes may reduce morbidity
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GP6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016363.5. 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 | 11 | 37 | 1 | 49 | ||
| missense | 1 | 67 | 30 | 1 | 99 | |
| nonsense | 6 | 1 | 1 | 8 | ||
| start loss | 0 | |||||
| frameshift | 6 | 3 | 1 | 10 | ||
| splice donor/acceptor (+/-2bp) | 4 | 1 | 5 | |||
| Total | 12 | 9 | 81 | 67 | 2 | 171 |
Highest pathogenic variant AF is 0.0008146733
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057447.5 | 8 | MANE Select | |
| Ensembl | ENSP00000394922.1 | 8 | MANE Select | |
| RefSeq | NP_001077368.2 | 8 | Standard | |
| RefSeq | NP_001242946.2 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
- Platelet Adhesion to exposed collagen
- GPVI-mediated activation cascade
Biological Process
- enzyme linked receptor protein signaling pathway
- blood coagulation
- platelet activation
- leukocyte migration
Molecular Function
- transmembrane signaling receptor activity
- protein binding
- collagen binding
- signaling receptor activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell surface
- extracellular exosome
- tetraspanin-enriched microdomain
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000310373
- Coding exons
- 8
- Length
- 24560
- Individuals with no LoFs
- 124745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 124796
- p
- 0.000204
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.415 | 379 | 357 | 1.06 | 0.0000227 | 3880 |
| Missense (PolyPhen) | 80 | 78.532 | 1.0187 | 794 | ||
| Synonymous | -1.21 | 178 | 159 | 1.12 | 0.0000116 | 1341 |
| Loss of Function | -0.241 | 16 | 15.0 | 1.07 | 7.37e-7 | 169 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00045 | 0.00045 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000080 | 0.000079 | rare |
| South Asian | 0.00065 | 0.00065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Collagen receptor involved in collagen-induced platelet adhesion and activation. Plays a key role in platelet procoagulant activity and subsequent thrombin and fibrin formation. This procoagulant function may contribute to arterial and venous thrombus formation. The signaling pathway involves the FcR gamma- chain, the Src kinases (likely FYN or LYN) and SYK, the adapter protein LAT and leads to the activation of PLCG2. {ECO:0000269|PubMed:10961879, ECO:0000269|PubMed:18955485}.;
- Disease
- DISEASE: Bleeding disorder, platelet-type 11 (BDPLT11) [MIM:614201]: A mild to moderate bleeding disorder caused by defective platelet activation and aggregation in response to collagen. {ECO:0000269|PubMed:19549989, ECO:0000269|PubMed:19552682}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.957
- RVIS EVS
- 2.13
- RVIS percentile EVS
- 97.94
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.607
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |