Gene Validity Curation

GP1BA - Bernard-Soulier syndrome

Gene: GP1BA (HGNC:4439)
Classification - 05/27/2020
Disease: Bernard-Soulier syndrome (MONDO_0009276)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: 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.
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
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 7
10.5
12
Kunishima S et al. 1994 Nov 15 (PMID:7949089); Afshar-Kharghan V et al. 1997 Oct 1 (PMID:9326230); Kenny D et al. 1998 Jul 1 (PMID:9639514); Afshar-Kharghan V et al. 2000 Sep (PMID:11054083); Vettore S et al. 2011 Dec (PMID:21993687); Bowers MJ et al. 2006 Jul (PMID:16788318); Imai C et al. 2009 Sep (PMID:19448529);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
2.25
de la Salle C et al. 1995 Feb (PMID:7873390); Li C et al. 1995 Nov 15 (PMID:7579348); Rosenberg N et al. 2007 Feb (PMID:17083647);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
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
1
Vanhoorelbeke K et al. 2000 Jan (PMID:10669163);
Protein Interaction 0.5 0 - 2 1 0.5
López JA et al. 1994 Sep 23 (PMID:8089142);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Ware J et al. 2000 Mar 14 (PMID:10706630);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
4
Ware J et al. 2000 Mar 14 (PMID:10706630); Kanaji S et al. 2012 Mar (PMID:22044935);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 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 12 5 17 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 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.