GP1BA

protein-coding

glycoprotein Ib platelet subunit alpha, the group of CD molecules

Gene summary

Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

Previous symbols:

GP1B

MANE transcript

NM_000173.7

Inheritance

AD, AR, SD

ClinVar variants

P:101U:189B:85

Top phenotype

Bernard-Soulier syndrome, type A2; Bernard-Soulier syndrome, type A1; von Willebrand disease, platelet-type

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr17:4,932,277-4,935,023

External References & Databases

Ensembl (ENSG00000185245)

Transcript & Mutation Effects

hg38 • Region Span ~2.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

platelet-type von Willebrand diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008332

Submitter: ClinGen

GP1BA was first reported in relation to autosomal dominant platelet-type von Willebrand disease in 1991 (Miller JL, et al., 1991, PMID: 2052556). At least 7 unique variants have been reported in humans; six missense mutations, located within the VWF binding region and one 27 bp deletion in the macroglycopeptide region. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 23 probands in 18 publications (PMIDs: 26116638, 16704444, 23014764, 17916098, 26988807, 19951970, 9282797, 27683759, 14521605, 25985451, 2052556, 17264965, 15705799, 8384898, 27819553, 7833477, 17233824, 24474090). Variants in this gene segregated with disease in 31 additional family members. Platelet-type von Willebrand disease is an inherited bleeding disorder caused by heterozygous gain-of-function variants of GP1BA conferring enhanced affinity for von Willebrand factor to platelet integrin GPIbα. This disorder is characterized by a mild to moderate bleeding phenotype associated with fluctuating thrombocytopenia. This gene-disease relationship is supported by its function in primary hemostasis, binding vWF, functional alteration in patient cells (PMID: 9226170, 30655369), and a knock-in mouse model (PMID: 18187573). In summary, GP1BA is definitively associated with autosomal dominant platelet-type von Willebrand disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note this gene has also been implicated in Bernard-Soulier Syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (gain of function vs. loss of function), inheritance pattern (autosomal dominant vs. predominantly autosomal recessive), and phenotypic variability. Therefore, we have split curations for the disease entities platelet-type von Willebrand disease and Bernard-Soulier Syndrome; these gene-disease relationships have been assessed separately.

autosomal dominant macrothrombocytopeniaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: Orphanet

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: Ambry Genetics

platelet-type von Willebrand diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008332

Submitter: Orphanet

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: ClinGen

GP1BA was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1991 (Ware et al., PMID: 2308962). At least 45 unique variants (e.g. missense, nonsense, and frameshifts) have been reported in humans (PMID: 24934643). The unifying feature of all of the mutations is the ability of the mutation to disrupt the assembly and/or function of a surface-expressed GP Ib-IX-V complex. How individual mutations affect complex assembly or surface expression can be variable. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 10 publications (PMIDs: 9326230, 11054083, 16788318, 7873390, 19448529, 9639514, 7949089, 7579348, 17083647, 21993687). Variants in this gene segregated with disease in 6 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease association is supported by its biochemical function in the GP1b platelet receptor for VWF (PMID: 10669163), its interaction with GP1BB (PMID: 808914), a knock-out animal model (PMID: 10706630), and rescue of the animal model with wildtype GP1BA (PMID: 10706630, 22044935). In summary, GP1BA is definitively associated with autosomal recessive Bernard-Soulier syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in autosomal dominant Bernard-Soulier syndrome (MONDO:0007930) characterized predominantly by macrothrombocytopenia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found interfamilial phenotypic variability is observed between individuals harboring the same genetic variant between different inheritance patterns and the difference in the inheritance pattern for the disease entities is representative of a continuum of disease, i.e. mild carrier phenotypic features are observed in recessive disease (PMID: 25370924). Thus the disease entities were lumped and the well-established autosomal recessive inheritance pattern has been curated here; additional mono-allelic manifestations have also been reported (PMIDs: 21933849, 18815197, 26849716, 16519708, 7690774). Additionally, this gene has also been implicated in platelet-type von Willebrand disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (gain of function vs. loss of function), inheritance pattern (autosomal dominant vs. predominantly autosomal recessive), and phenotypic variability. Therefore, we have split curations for the disease entities platelet-type von Willebrand disease and Bernard-Soulier Syndrome; these gene-disease relationships have been assessed separately.

platelet-type von Willebrand diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008332

Submitter: Ambry Genetics

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: PanelApp Australia

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: Labcorp Genetics (formerly Invitae)

Bernard-Soulier syndrome, type A2, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007930

Submitter: PanelApp Australia

platelet-type von Willebrand diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008332

Submitter: Labcorp Genetics (formerly Invitae)

Bernard-Soulier syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009276

Submitter: Orphanet

Bernard-Soulier syndrome, type A2, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007930

Submitter: Labcorp Genetics (formerly Invitae)

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0009276

Submitter: Ambry Genetics

platelet-type von Willebrand diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008332

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bernard-Soulier syndrome, type A2; Bernard-Soulier syndrome, type A1; von Willebrand disease, platelet-typeAD/AR

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Preventive measures (eg, in the case of surgery) and treatment of bleeding episodes can be beneficial; Specific medications (eg, certain anesthetics) that interfere with platelet function should be avoided

Refs: 18116504; 14081293; 6019024; 6286015; 6798442; 6333901; 2308962; 2052556; 1901273; 1730088; 8384898; 9616133; 11222377; 14711733; 21173099; 22102188; 23014764

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GP1BA variants in ClinVar

15 Conditions Cataloged

not providedTotal: 113

not specifiedTotal: 97

Inborn genetic diseasesTotal: 92

Bernard Soulier syndromeTotal: 91

GP1BA-related disorderTotal: 81

Bernard-Soulier syndrome, type A2, autosomal dominantTotal: 49

Pseudo von Willebrand diseaseTotal: 37

Nonarteritic anterior ischemic optic neuropathy, susceptibility toTotal: 25

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000173.7. 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			1 clinvar	60 clinvar	1 clinvar	62
missense	9 clinvar	23 clinvar	178 clinvar	19 clinvar	4 clinvar	233
nonsense	3 clinvar	14 clinvar	4 clinvar			21
start loss			1 clinvar			1
frameshift	7 clinvar	45 clinvar	5 clinvar	1 clinvar		58
splice donor/acceptor (+/-2bp)						0
Total	19	82	189	80	5	375

Highest pathogenic variant AF is 0.00011030487

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000173.7	RefSeq	NP_000164.5	1	MANE Select
ENST00000329125.6	Ensembl	ENSP00000329380.5	1	MANE Select
ENST00001141254.1	Ensembl	ENSP00000807199.1	1	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)
Hematopoietic cell lineage - Homo sapiens (human)
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
Gene expression (Transcription)

Biological Process

cell morphogenesis
cell adhesion
cell surface receptor signaling pathway
blood coagulation
blood coagulation, intrinsic pathway

Molecular Function

protein binding
thrombin-activated receptor activity

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane
cell surface
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329125
Coding exons: 1
Length: 2734
Individuals with no LoFs: 124505
Homozygous LoFs: 0
Heterozygous LoFs: 148
Defined: 124653
p: 0.000594

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.303	368	352	1.05	0.0000208	4149
Missense (PolyPhen)		68	73.815	0.92122		941
Synonymous	-0.811	178	165	1.08	0.0000105	1501
Loss of Function	0.463	4	5.13	0.779	2.67e-7	55

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0.00021	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00050	0.00044	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0011	0.00097	notable
South Asian	0.00010	0.000098	rare
Other	0.00069	0.00050	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.;
Disease: DISEASE: Non-arteritic anterior ischemic optic neuropathy (NAION) [MIM:258660]: An ocular disease due to ischemic injury to the optic nerve. It usually affects the optic disk and leads to visual loss and optic disk swelling of a pallid nature. Visual loss is usually sudden, or over a few days at most and is usually permanent, with some recovery possibly occurring within the first weeks or months. Patients with small disks having smaller or non- existent cups have an anatomical predisposition for non-arteritic anterior ischemic optic neuropathy. As an ischemic episode evolves, the swelling compromises circulation, with a spiral of ischemia resulting in further neuronal damage. {ECO:0000269|PubMed:14711733}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Bernard-Soulier syndrome (BSS) [MIM:231200]: A coagulation disorder characterized by a prolonged bleeding time, unusually large platelets, thrombocytopenia, and impaired prothrombin consumption. {ECO:0000269|PubMed:10089893, ECO:0000269|PubMed:1730088, ECO:0000269|PubMed:7690774, ECO:0000269|PubMed:7819107, ECO:0000269|PubMed:7873390, ECO:0000269|PubMed:9639514}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bernard-Soulier syndrome A2, autosomal dominant (BSSA2) [MIM:153670]: A coagulation disorder characterized by mild to moderate bleeding tendency, thrombocytopenia, and an increased mean platelet volume. Some individuals have no symptoms. Mild bleeding tendencies manifest as epistaxis, gingival bleeding, menorrhagia, easy bruising, or prolonged bleeding after dental surgery. {ECO:0000269|PubMed:11222377}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudo-von Willebrand disease (VWDP) [MIM:177820]: A bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor by the platelet glycoprotein Ib (GP Ib) receptor complex. Hemostatic function is impaired due to the removal of VWF multimers from the circulation. {ECO:0000269|PubMed:14521605, ECO:0000269|PubMed:2052556, ECO:0000269|PubMed:8384898, ECO:0000269|PubMed:8486780}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.550

Intolerance Scores

LoFtool: 0.630
RVIS EVS: 0.14
RVIS percentile EVS: 63.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.883

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium