ClinVar Miner

Submissions for variant NM_000506.5(F2):c.*97G>A (rs1799963)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205022 SCV000262466 pathogenic Prothrombin deficiency, congenital 2020-10-31 criteria provided, single submitter clinical testing This sequence change (rs1799963) is a common variant associated with prothrombin-related thrombophilia. It has historically been called prothrombin 20210G>A. As many as 1.7% to 3% of the general U.S. and European populations are heterozygous for this sequence change (PMID: 9569177, 20301327). Heterozygosity for this variant is associated with increased prothrombin levels, and a 2- to 4-fold increased risk of venous thrombosis over the baseline population (PMID: 19289024, 20301327). For these reasons, this variant has been classified as Pathogenic (low penetrance).
Counsyl RCV000014237 SCV000677907 pathogenic Thrombophilia due to thrombin defect 2015-08-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826090 SCV000967587 risk factor Venous thromboembolism 2019-12-04 criteria provided, single submitter clinical testing F2 c.*97G>A (also known as c.20210G>A or G20210A) has been associated with increased risk for venous thromboembolism. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Latino ancestry (1.8%, Genome Aggregation Database (gnomAD); rs121909293) and is present in ClinVar (ID: 13310). At least two large meta analyses has reported an odds ratio of 3.18-5.18 for developing venous thromboembolism (OR=3.18 [95% CI 2.19-3.46] Gohil 2009, OR=5.38 [95% CI 3.96-8.58] Gonzalez 2016). In vitro functional studies provide some evidence that the c.*97G>A variant may impact protein function (Gehring 2001, Danckwardt 2004). In summary, this variant is not expected to cause highly penetrant Mendelian disease. c.*97G>A variant is an established risk factor for venous thromboembolism.
Mendelics RCV000014237 SCV001138282 pathogenic Thrombophilia due to thrombin defect 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091960 SCV001248265 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000205022 SCV001251846 uncertain significance Prothrombin deficiency, congenital 2020-05-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000205022 SCV001262797 benign Prothrombin deficiency, congenital 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000022729 SCV001368932 uncertain significance Pregnancy loss, recurrent, susceptibility to, 2 2019-06-21 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS1.
OMIM RCV000014237 SCV000034485 pathogenic Thrombophilia due to thrombin defect 2009-06-17 no assertion criteria provided literature only
OMIM RCV000014238 SCV000034486 risk factor Ischemic stroke, susceptibility to 2009-06-17 no assertion criteria provided literature only
OMIM RCV000022729 SCV000044018 risk factor Pregnancy loss, recurrent, susceptibility to, 2 2009-06-17 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000991171 SCV001142420 risk factor Hereditary factor II deficiency disease 2020-01-06 no assertion criteria provided curation NM_000506.3:c.*97G>A was reported as 20210G>A in previous publications. NM_000506.3:c.*97G>A in the F2 gene has an allele frequency of 0.012 in European (non-Finnish) subpopulation in the gnomAD database. This variant is a common variant associated with prothrombin-related thrombophilia (PMID: 9569177, 20301327). Heterozygosity for this variant is associated with increased prothrombin levels, and a 2- to 4-fold increased risk of venous thrombosis over the baseline population (PMID: 19289024). Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (PMID: 9569177). For these reasons, this variant has been classified as At-risk. Taken together, we interprete this variant as a risk factor.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000205022 SCV001552413 pathogenic Prothrombin deficiency, congenital no assertion criteria provided clinical testing The F2 3' UTR c.*97G>A variant was identified in dbSNP (rs1799963) and Clinvar (classified as pathogenic by Counsyl and Mendelics in relation to venous thrombosis; mixed predictions of pathogenicity in association with congenital prothrombin deficiency). The F2 3' UTR c.*97G>A variant, historically called the prothrombin 20210G>A variant, is associated with increased prothrombin levels in the heterozygous state and has been found to be associated with a 2- to 3-fold increased risk of venous thrombosis over the baseline population (Foy_2009_19289024; Ho_2006_16606808). However, the estimated population attributable risk of recurrence  for venous thromboembolism is modest (approximately 6.7%; 5% CI, 3.4-9.9%) and likely does not warrant extended anticoagulation treatment (Ho_2006_16606808). The prothrombin 20210G>A variant disrupts the F2 cleavage signal within the 3' UTR, causing increased cleavage site recognition and subsequently increased 3′ end processing, mRNA accumulation, protein synthesis, and ultimately elevated plasma prothrombin concentrations (Gehring_2001_11443298). The variant was identified in control databases in 265 of 31396 chromosomes (1 homozygous) at a frequency of 0.8441%, and was observed at the highest frequency  in the Latino population in 15 of 848 chromosomes (freq: 0.01769) (Genome Aggregation Database March 6, 2019, v2.1.1). The The F2 3' UTR c.*97G>A variant is not conserved in mammals. In silico predictions predicting the impact of the The F2 3' UTR c.*97G>A variant to the protein are not available. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.