Gene Validity Curation

GP1BB - Bernard-Soulier syndrome

Gene: GP1BB (HGNC:4440)
Classification - 06/06/2019
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: 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).
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 5
11
12
Moran N et al. 2000 Jul 15 (PMID:10887115); Kunishima S et al. 2002 Dec (PMID:12447957); Watanabe R et al. 2003 Jun (PMID:12945881); Strassel C et al. 2006 Jan (PMID:16409472); Kunishima S et al. 2006 Dec (PMID:16978236);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3
Kunishima S et al. 1997 Apr 1 (PMID:9116284); Strassel C et al. 2003 Apr 22 (PMID:12693941); González-Manchón C et al. 2003 Sep (PMID:12958615);
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
1.5
Moake JL et al. 1988 May (PMID:3258770);
Protein Interaction 0.5 0 - 2 1 1
López JA et al. 1994 Sep 23 (PMID:8089142);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Strassel C et al. 2006 Jan (PMID:16409472);
Models Non-human model organism 2 0 - 4 4 1 3 4
Kato K et al. 2004 Oct 15 (PMID:15213102);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
1.5
Strassel C et al. 2016 July (PMID:27148783);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 6 18 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
11/13/2019
EXPERT CURATION (DATE)
Definitive
06/06/2019
EVIDENCE SUMMARY
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).