Gene Validity Curation

FGB - congenital fibrinogen deficiency

Gene: FGB (HGNC:3662)
Classification - 01/22/2020
Disease: congenital fibrinogen deficiency (MONDO_0018060)
Mode of Inheritance: Semidominant inheritance (HP:0032113)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between FGB and congenital fibrinogen deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. More than a 30 pathogenic variants in this gene are reported in humans, ranging from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital fibrinogen deficiency is characterized by quantitative and qualitative defects in fibrinogen. It may manifest as afibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Clinical symptoms include a bleeding diathesis and/or a thrombotic phenotype. Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 8 publications (PMID: 23266225, 25629419, 24560896, 15070683, 12893758, 12161363, 23560673, 12511408). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease have been reported to be heterozygous as well as biallelic loss of function (PMID: 23266225, PMID:15070683). Summary of Experimental Data (3 points): FGB encodes the β subunit of the coagulation factor, fibrinogen, which is a hexamer of three subunit chains (PMID: 22836683). The Bβ fibrinopeptide along with Aα fibrinopeptide interact with thrombin, which catalyzes the conversion of fibrinogen to fibrin (PMID: 15572239). It is synthesized in the liver and secreted into the plasma (PMID: 20921339). A zebrafish model that recapitulate fibrinogen deficiency is reported (PMID: 24098662). In summary, the FGB-Congenital fibrinogen deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on January 22, 2020. (SOP Version 7) Lumping & Splitting information: OMIM assertions - (1) Congenital Afibrinogenemia (MIM: 202400); (2) Congenital Dysfibrinogenemia (MIM: 616004); (3) Congenital Hypofibrinogenemia (MIM: 202400). Orphanet assertions - (1) Familial afibrinogenemia; (2) Familial dysfibrinogenemia; (3) Familial hypodysfibrinogenemia; (4) Familial hypofibrinogenemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: Congenital Afibrinogenemia, Congenital Dysfibrinogenemia, Congenital Hypodysfibrinogenemia and Congenital Hypofibrinogenemia. These entities have been lumped together under Congenital Fibrinogen Deficiency.
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 2 2.5 2.5
Marchi R et al. 2013 Mar (PMID:23266225); Priovolos A et al. 2015 Mar (PMID:25629419);
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 6
10.5
11
Asselta R et al. 2004 Apr 15 (PMID:15070683); Vu D et al. 2003 Dec 15 (PMID:12893758); Asselta R et al. 2002 Aug (PMID:12161363); Sumitha E et al. 2013 Jul (PMID:23560673); Neerman-Arbez M et al. 2003 May 1 (PMID:12511408); Casini A et al. 2014 May (PMID:24560896);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
0.5
Casini A et al. 2014 May (PMID:24560896);
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 2
1.5
2
Fish RJ et al. 2012 Sep (PMID:22836683); Scheraga HA et al. 2004 Dec 20 (PMID:15572239);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Fort A et al. 2011 Jan 6 (PMID:20921339);
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 1 1
Vo AH et al. 2013 Sep 30 (PMID:24098662);
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) 3

 


 

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 3 15 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
01/23/2020
EXPERT CURATION (DATE)
Definitive
01/22/2020
EVIDENCE SUMMARY
The relationship between FGB and congenital fibrinogen deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. More than a 30 pathogenic variants in this gene are reported in humans, ranging from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital fibrinogen deficiency is characterized by quantitative and qualitative defects in fibrinogen. It may manifest as afibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Clinical symptoms include a bleeding diathesis and/or a thrombotic phenotype. Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 8 publications (PMID: 23266225, 25629419, 24560896, 15070683, 12893758, 12161363, 23560673, 12511408). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease have been reported to be heterozygous as well as biallelic loss of function (PMID: 23266225, PMID:15070683). Summary of Experimental Data (3 points): FGB encodes the β subunit of the coagulation factor, fibrinogen, which is a hexamer of three subunit chains (PMID: 22836683). The Bβ fibrinopeptide along with Aα fibrinopeptide interact with thrombin, which catalyzes the conversion of fibrinogen to fibrin (PMID: 15572239). It is synthesized in the liver and secreted into the plasma (PMID: 20921339). A zebrafish model that recapitulate fibrinogen deficiency is reported (PMID: 24098662). In summary, the FGB-Congenital fibrinogen deficiency gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on January 22, 2020. (SOP Version 7) Lumping & Splitting information: OMIM assertions - (1) Congenital Afibrinogenemia (MIM: 202400); (2) Congenital Dysfibrinogenemia (MIM: 616004); (3) Congenital Hypofibrinogenemia (MIM: 202400). Orphanet assertions - (1) Familial afibrinogenemia; (2) Familial dysfibrinogenemia; (3) Familial hypodysfibrinogenemia; (4) Familial hypofibrinogenemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: Congenital Afibrinogenemia, Congenital Dysfibrinogenemia, Congenital Hypodysfibrinogenemia and Congenital Hypofibrinogenemia. These entities have been lumped together under Congenital Fibrinogen Deficiency.