Gene Validity Curation

GP9 - Bernard-Soulier syndrome

Gene: GP9 (HGNC:4444)
Classification - 11/27/2019
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: GP9 was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1993 Wright SD, et al., 1993, PMID: 8481514). At least 32 unique variants (primarily missense, with some 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 36 probands in 12 publications (PMIDs: 8481514, 23143686, 9432024, 21699652, 21173099, 21113250, 9886312, 12100158, 10583255, 16916536, 15609295, 23995613). 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 and experimental evidence has been reached. This gene-disease association is supported by its reduced expression in patient cells (PMID: 9432024), its protein interactions with GP1BB (PMID: 808914), functional alteration in non-patient cells (PMID: 10527407, PMID: 8608225), and a knock-out animal model (PMID: 28650483). In summary, GP9 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.
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
4
12
Takata Y et al. 2012 Dec (PMID:23143686); Sandrock K et al. 2010 Sep 15 (PMID:21113250); Savoia A et al. 2011 Mar (PMID:21173099); Ali S et al. 2014 Mar (PMID:23995613); Sumitha E et al. 2011 Aug (PMID:21699652);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 29
10.05
Suzuki K et al. 1997 Dec (PMID:9432024); Wright SD et al. 1993 May 1 (PMID:8481514); Kunishima S et al. 1999 Dec (PMID:10583255); Lanza F et al. 2002 Jul (PMID:12100158); Noris P et al. 1998 Dec (PMID:9886312); Drouin J et al. 2005 Jan (PMID:15609295); Gohda F et al. 2006 Aug 17 (PMID:16916536); Savoia A et al. 2011 Mar (PMID:21173099); Ali S et al. 2013 Feb 12 (PMID:23402648); Ali S et al. 2014 Mar (PMID:23995613); Sumitha E et al. 2011 Aug (PMID:21699652);
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
0.5
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 2
Meehan TF et al. 2017 Aug (PMID:28650483);
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) 2.5

 


 

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 2.5 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
11/18/2019
EXPERT CURATION (DATE)
Definitive
11/27/2019
EVIDENCE SUMMARY
GP9 was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1993 Wright SD, et al., 1993, PMID: 8481514). At least 32 unique variants (primarily missense, with some 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 36 probands in 12 publications (PMIDs: 8481514, 23143686, 9432024, 21699652, 21173099, 21113250, 9886312, 12100158, 10583255, 16916536, 15609295, 23995613). 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 and experimental evidence has been reached. This gene-disease association is supported by its reduced expression in patient cells (PMID: 9432024), its protein interactions with GP1BB (PMID: 808914), functional alteration in non-patient cells (PMID: 10527407, PMID: 8608225), and a knock-out animal model (PMID: 28650483). In summary, GP9 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.