Gene Validity Curation

GP1BA - pseudo-von Willebrand disease

Gene: GP1BA (HGNC:4439)
Classification - 05/27/2020
Disease: pseudo-von Willebrand disease (MONDO_0008332)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: 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.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 1
2.5
2.5
Kunishima S et al. 1997 Jul (PMID:9282797);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 22
9.3
7
Miller JL et al. 1991 Jun 1 (PMID:2052556); Russell SD et al. 1993 Apr 1 (PMID:8384898); Matsubara Y et al. 2003 Oct (PMID:14521605); Othman M et al. 2005 Jun 1 (PMID:15705799); Enayat S et al. 2012 Nov (PMID:23014764); Woods AI et al. 2014 Mar (PMID:24474090); Lavenu-Bombled C et al. 2016 Nov 30 (PMID:27683759); Takahashi H et al. 1995 Feb 1 (PMID:7833477); Enayat MS et al. 2006 Jun (PMID:16704444); Favaloro EJ et al. 2007 Nov (PMID:17916098); Giannini S et al. 2010 Jun (PMID:19951970); Maurer M et al. 2015 May (PMID:25985451); Desai DS et al. 2015 Jul (PMID:26116638); Fidalgo T et al. 2016 July 4 (PMID:26988807); Nurden P et al. 2007 Feb (PMID:17264965); Whalley IN et al. 2007 Jan (PMID:17233824); Sánchez-Luceros A et al. 2017 Jul (PMID:27819553);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.53 1
Miller JL et al. 1991 Jun 1 (PMID:2052556);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.53    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 10
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Vanhoorelbeke K et al. 2000 Jan (PMID:10669163);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Moriki T et al. 1997 Jul 15 (PMID:9226170); Bury L et al. 2019 July (PMID:30655369);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Suva LJ et al. 2008 Feb (PMID:18187573);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 10 4.5 14.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/27/2020
EXPERT CURATION (DATE)
Definitive
05/27/2020
EVIDENCE SUMMARY
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.