GP1BB

protein-coding

glycoprotein Ib platelet subunit beta, the group of CD molecules

Gene summary

Platelet glycoprotein Ib (GPIb) is a heterodimeric transmembrane protein consisting of a disulfide-linked 140 kD alpha chain and 22 kD beta chain. It is part of the GPIb-V-IX system that constitutes the receptor for von Willebrand factor (VWF), and mediates platelet adhesion in the arterial circulation. GPIb alpha chain provides the VWF binding site, and GPIb beta contributes to surface expression of the receptor and participates in transmembrane signaling through phosphorylation of its intracellular domain. Mutations in the GPIb beta subunit have been associated with Bernard-Soulier syndrome, velocardiofacial syndrome and giant platelet disorder. The 206 amino acid precursor of GPIb beta is synthesized from a 1.0 kb mRNA expressed in plateletes and megakaryocytes. A 411 amino acid protein arising from a longer, unspliced transcript in endothelial cells has been described; however, the authenticity of this product has been questioned. Yet another less abundant GPIb beta mRNA species of 3.5 kb, expressed in nonhematopoietic tissues such as endothelium, brain and heart, was shown to result from inefficient usage of a non-consensus polyA signal in the neighboring upstream gene (SEPT5, septin 5). In the absence of polyadenylation from its own imperfect site, the SEPT5 gene produces read-through transcripts that use the consensus polyA signal of this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_000407.5

Inheritance

AD, AR

ClinVar variants

P:46U:79B:35

Top phenotype

Bernard-Soulier syndrome; Giant platelet disorder, isolated

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr22:19,723,539-19,724,771

External References & Databases

Ensembl (ENSG00000203618)

Transcript & Mutation Effects

hg38 • Region Span ~1.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bernard-Soulier syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009276

Submitter: Orphanet

autosomal dominant macrothrombocytopeniaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: Orphanet

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: ClinGen

GP1BB was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1997 (Kunishima et al., PMID: 9116284). At least 33 unique variants (e.g. missense, nonsense, and frameshifts) have been reported in humans. 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 8 probands in 8 publications (PMIDs: 9116284, 12693941, 12958615, 10887115, 12447957, 12945881, 16409472, 16978236). Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease association is supported by its biochemical function in the GP1b platelet receptor for VWF (PMID: 3258770), its protein interactions with GP1BA and GP9 (PMID: 808914), functional alteration in non-patient cells (PMID: 16409472), a knock-out animal model (PMID: 15213102), and rescue of the animal model with human GP1BB (PMID: 27148783). In summary, GP1BB 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 isolated inherited macrothrombocytopenia (MONDO:0016361). 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. 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: 28064200, 30609015, 25370924, 29527674).

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: Ambry Genetics

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: Labcorp Genetics (formerly Invitae)

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: PanelApp Australia

autosomal dominant macrothrombocytopeniaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bernard-Soulier syndrome; Giant platelet disorder, isolatedAR

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; 1901273; 8703016; 9116284; 9616133; 21173099; 21800012; 22102188

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GP1BB variants in ClinVar

13 Conditions Cataloged

not specifiedTotal: 65

Bernard Soulier syndromeTotal: 61

not providedTotal: 50

GP1BB-related disorderTotal: 19

MacrothrombocytopeniaTotal: 12

ThrombocytopeniaTotal: 9

GP1BB-related disordersTotal: 6

Mild macrothrombocytopeniaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000407.5. 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				30 clinvar		30
missense	1 clinvar	16 clinvar	79 clinvar	2 clinvar	3 clinvar	101
nonsense	2 clinvar	6 clinvar				8
start loss	1 clinvar	4 clinvar				5
frameshift	4 clinvar	12 clinvar				16
splice donor/acceptor (+/-2bp)						0
Total	8	38	79	32	3	160

Highest pathogenic variant AF is 0.000021010352

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000407.5	RefSeq	NP_000398.1	2	MANE Select
ENST00000366425.4	Ensembl	ENSP00000383382.2	2	MANE Select
ENST00000909123.1	Ensembl	ENSP00000579182.1	2	Standard
ENST00001129079.1	Ensembl	ENSP00000798884.1	2	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)
Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
GP1b-IX-V activation signalling

Biological Process

cell adhesion
cell surface receptor signaling pathway
blood coagulation
blood coagulation, intrinsic pathway
platelet activation

Molecular Function

transmembrane signaling receptor activity
protein binding
identical protein binding

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366425
Coding exons: 2
Length: 1827
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	0.459	53	63.3	0.838	0.00000341	1195
Missense (PolyPhen)		10	14.602	0.68482		381
Synonymous	-0.641	41	36.1	1.14	0.00000198	540
Loss of Function	1.33	0	2.05	0.00	8.84e-8	28

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: dbNSFP

Function: FUNCTION: Gp-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to von Willebrand factor, which is already bound to the subendothelium.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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