Gene Validity Curation

PROS1 - hereditary thrombophilia due to congenital protein S deficiency

Gene: PROS1 (HGNC:9456)
Classification - 01/22/2020
Disease: hereditary thrombophilia due to congenital protein S deficiency (MONDO_0019144)
Mode of Inheritance: Semidominant inheritance (HP:0032113)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: PROS1 was first reported in relation to semidominant hereditary thrombophilia due to congenital protein S deficiency in 1994 (Hayashi T, et al., 1994, PMID: 8298131). Over 400 unique variants (including missense, nonsense, splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 5 publications (PMIDs: 8298131, 10063989, 7545463, 20484936, 10447256). Variants in this gene segregated with disease in 33 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 relationship is supported by its biochemical function as a cofactor for Protein C (PMID: 6892911), and both heterozygous and null mouse models which recapitulate phenotypes observed in humans (PMID: 19567881). In summary, PROS1 is definitively associated with semidominant hereditary thrombophilia due to congenital protein S deficiency. 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 9 14.5 10
Formstone CJ et al. 1995 Oct 1 (PMID:7545463); Espinosa-Parrilla Y et al. 1999 (PMID:10447256);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
1.7
1.7
Hayashi T et al. 1994 Feb 1 (PMID:8298131); Formstone CJ et al. 1995 Oct 1 (PMID:7545463); Espinosa-Parrilla Y et al. 1999 (PMID:10447256);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 1
2
2.5
Pung-amritt P et al. 1999 Feb (PMID:10063989);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
0.5
Espinosa-Parrilla Y et al. 1999 (PMID:10447256); Fischer D et al. 2010 May 20 (PMID:20484936);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.12 3
Formstone CJ et al. 1995 Oct 1 (PMID:7545463); Espinosa-Parrilla Y et al. 1999 (PMID:10447256);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.12    
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
Walker FJ et al. 1980 Jun 25 (PMID:6892911);
Protein Interaction 0.5 0 - 2
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 3 3
Saller F et al. 2009 Sep 10 (PMID:19567881);
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) 3.5

 


 

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 3.5 15.5 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
12/26/2019
EXPERT CURATION (DATE)
Definitive
01/22/2020
EVIDENCE SUMMARY
PROS1 was first reported in relation to semidominant hereditary thrombophilia due to congenital protein S deficiency in 1994 (Hayashi T, et al., 1994, PMID: 8298131). Over 400 unique variants (including missense, nonsense, splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 5 publications (PMIDs: 8298131, 10063989, 7545463, 20484936, 10447256). Variants in this gene segregated with disease in 33 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 relationship is supported by its biochemical function as a cofactor for Protein C (PMID: 6892911), and both heterozygous and null mouse models which recapitulate phenotypes observed in humans (PMID: 19567881). In summary, PROS1 is definitively associated with semidominant hereditary thrombophilia due to congenital protein S deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.