Gene Validity Curation

F2 - congenital prothrombin deficiency

Gene: F2 (HGNC:3535)
Classification - 06/24/2020
Disease: congenital prothrombin deficiency (MONDO_0013361)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between F2 and congenital prothrombin deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. At least 15 causative variants in this gene are reported in humans, ranging from deletions, frameshift and missense variants. Congenital prothrombin deficiency is rare and is characterized by a bleeding diathesis due to reduced Factor II activity. Mutations in F2 were first associated with this disease in humans as early as 1992 by Iwahana et al and Morishita et al. (PMID: 1334372 & 1421398). Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 8 publications (PMID: 1334372, 1421398, 12149217, 12492590, 6405779, 8839854, 7740448, 16543981). Variants segregated with disease in at least 8 additional family members. 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 biallelic loss of function. Summary of Experimental Data (5 points): Prothrombin is cleaved to yield thrombin that is essential to convert fibrin to fibrinogen for efficient clot formation. (PMID: 16006504). Mouse models that have the F2 gene knocked out show embryonic and perinatal lethality with massive hemorrhage and no clottable blood (PMID: 9636196, 9636195). In summary, the F2-Congenital prothrombin 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 June 24, 2020. (SOP Version 6)
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 4
8.5
10.75
Stanchev H et al. 2006 Jan (PMID:16543981); Akhavan S et al. 2003 Jan (PMID:12492590); O'Marcaigh AS et al. 1996 Oct 1 (PMID:8839854); Iwahana H et al. 1992 Dec (PMID:1334372);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
2.25
Board PG et al. 1983 Jun (PMID:6405779); Morishita E et al. 1992 Nov 1 (PMID:1421398); Akhavan S et al. 2002 Aug 15 (PMID:12149217); O'Marcaigh AS et al. 1996 Oct 1 (PMID:8839854); Poort SR et al. 1994 Dec (PMID:7740448);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.82 2
O'Marcaigh AS et al. 1996 Oct 1 (PMID:8839854); Poort SR et al. 1994 Dec (PMID:7740448);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.82    
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
0.5
Bianchini EP et al. 2005 Jul 19 (PMID:16006504);
Protein Interaction 0.5 0 - 2
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
Bianchini EP et al. 2005 Jul 19 (PMID:16006504);
Models Non-human model organism 2 0 - 4 4 2 4 4
Sun WY et al. 1998 Jun 23 (PMID:9636195); Xue J et al. 1998 Jun 23 (PMID:9636196);
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) 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
06/24/2020
EXPERT CURATION (DATE)
Definitive
06/24/2020
EVIDENCE SUMMARY
The relationship between F2 and congenital prothrombin deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. At least 15 causative variants in this gene are reported in humans, ranging from deletions, frameshift and missense variants. Congenital prothrombin deficiency is rare and is characterized by a bleeding diathesis due to reduced Factor II activity. Mutations in F2 were first associated with this disease in humans as early as 1992 by Iwahana et al and Morishita et al. (PMID: 1334372 & 1421398). Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 8 publications (PMID: 1334372, 1421398, 12149217, 12492590, 6405779, 8839854, 7740448, 16543981). Variants segregated with disease in at least 8 additional family members. 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 biallelic loss of function. Summary of Experimental Data (5 points): Prothrombin is cleaved to yield thrombin that is essential to convert fibrin to fibrinogen for efficient clot formation. (PMID: 16006504). Mouse models that have the F2 gene knocked out show embryonic and perinatal lethality with massive hemorrhage and no clottable blood (PMID: 9636196, 9636195). In summary, the F2-Congenital prothrombin 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 June 24, 2020. (SOP Version 6)