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

gnomAD frequency: 0.00979  dbSNP: rs1799963

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205022	SCV000262466	pathogenic, low penetrance	Congenital prothrombin deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the F2 gene. It does not change the encoded amino acid sequence of the F2 protein. This variant is present in population databases (rs1799963, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. 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). ClinVar contains an entry for this variant (Variation ID: 13310). 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, Mass General Brigham 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 Center for Human Genetics Tuebingen	RCV001091960	SCV001248265	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	F2: PS3:Very Strong, PP1:Strong
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000205022	SCV001251846	uncertain significance	Congenital prothrombin deficiency	2020-05-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001091960	SCV001262797	pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	The F2 c.*97G>A variant, previously known as prothrombin 20210G>A or G20210A, occurs in the 3' untranslated region of the F2 gene and results in the substitution of a guanine at nucleotide position c.*97 with an adenine. The c.*97G>A variant is a well-documented variant associated with an increased risk of venous thromboembolism (VTE). Across a selection of the available literature, heterozygosity for the c.*97G>A variant has been estimated to confer an increased risk of VTE between 1.9 to 11.5 fold, with the majority of estimates falling between 2 and 5 fold. Homozygosity for this variant is presumed to confer a higher risk of VTE, however the magnitude of this risk is not well defined (PMID: 20301327; PMID: 30297698). Data from a 2009 meta-analysis indicated that while heterozygosity for the c.*97G>A variant confers an increased risk for initial VTE, it was not predictive of recurrent events (PMID: 19531787). The highest frequency of this allele in the Genome Aggregation Database is 0.03165 in the Middle Eastern population (version 3.1.2). This frequency is high but is consistent with disease prevalence estimates and incomplete penetrance among variant carriers. Functional studies indicate that the c.*97G>A variant enhances 3' end processing of pre-mRNA, which results in increased mRNA production and elevated prothrombin levels (PMID: 8916933; PMID: 15059842). Based on the collective evidence, the c.*97G>A variant is classified as pathogenic with reduced penetrance for thrombophilia due to thrombin defect.
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.
Neurogenetics Research Program, University of Adelaide	RCV001794446	SCV001737608	risk factor	Cerebral palsy	2021-06-10	criteria provided, single submitter	research	Heterozygosity for F2 c.*97G>A (G20210A, rs1799963) is the second most common genetic risk factor for venous thrombosis
GeneDx	RCV001091960	SCV001822471	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Also known as 20210G>A and G20210A due to alternate nomenclature; Published functional studies demonstrate elevated plasma levels of prothrombin (Danckwardt et al., 2004); This variant is associated with the following publications: (PMID: 22909823, 26732783, 29431110, 25528068, 26422681, 25772935, 15059842, 22021457, 19356951, 22023246, 20723024, 24619398, 11583312, 8916933, 25977387, 22141575, 27031503, 19652888, 15726653, 28707429, 22023244, 31472339, 25028703, 32155011, 26148378, 24016568, 25693916, 29974397, 30005273, 26226452, 34570182, 16411414, 9238178, 11684865, 10456622, 25509247, 11864707, 10507841, 33258288, 11737249, 11064483, 10406905, 11190909, 11114826)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000014237	SCV002500854	pathogenic	Thrombophilia due to thrombin defect		criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000014237	SCV003806787	pathogenic	Thrombophilia due to thrombin defect	2022-08-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PP1 strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014237	SCV003844696	pathogenic	Thrombophilia due to thrombin defect	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: F2 c.*97G>A (also known as c.20210G>A or G20210A) is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0096 in 150958 control chromosomes in the gnomAD database (v3.1 genomes dataset), including 18 homozygotes. Heterozygosity for this variant is associated with increased prothrombin levels (e.g. Gehring_2001, Foy_2009), and several meta analyses reported 2- to 4-fold increased risk of venous thrombosis (e.g. Kujovich_2006, Ho_2006, Foy_2009, Gonzalez_2016, Shemes_2017, Baylis_2021), describing this variant as the second most common inherited thrombophilic risk factor. In addition, a recent study reported an even higher relative risk for venous thromboembolism (OR = 5 (95% CI 2.1-11.92)) for homozygous individuals (Shemes_2017). At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant caused increased cleavage site recognition and subsequently increased 3' end processing, mRNA accumulation, and increased protein synthesis (Gehring_2001), which can explain the elevated prothrombin plasma concentrations. 12 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=5), VUS (n=2), benign (n=1), or risk factor (n=4). Based on the evidence outlined above, the variant represents a well-known hypermorphic mutation, which causes an increase in normal gene function, resulting in an increased risk of thrombophilia, therefore it was classified as a 'low penetrance pathogenic' (i.e. risk) variant.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014237	SCV003921890	pathogenic	Thrombophilia due to thrombin defect	2020-07-22	criteria provided, single submitter	clinical testing	0101 - Gain of function is a known mechanism of disease in this gene and is associated with thrombophilia due to a thrombin defect (MIM#188050) (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. However, this variant is described to be semi-dominant as both homozygotes and heterozygotes are at increased risk for venous thromboembolism, with homozygotes having a greater risk (OMIM, PMID: 30297698). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30297698). (I) 0217 - Non-coding variant with known effect. The c.*97G>A results in gain-of-function with elevated protein synthesis (PMID: 11443298). (SP) 0251 - This variant is heterozygous. (I) 0303 - Variant is present in gnomAD (v3) >=0.01 for a dominant condition (1343 heterozygotes, 17 homozygotes). (SB) 0504 - Same nucleotide change has been observed in placental mammals. (SB) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic for venous thromboembolism and as a risk factor for both stroke and recurrent pregnancy loss (ClinVar; PMID: 30297698). A review study showed this variant is more prevalent in affected Italian, Brazilian and German individuals (PMID: 27031503). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000014237	SCV004040661	pathogenic	Thrombophilia due to thrombin defect	2023-07-27	criteria provided, single submitter	clinical testing
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	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	RCV000205022	SCV001142420	risk factor	Congenital prothrombin deficiency	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	Congenital prothrombin deficiency		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.
GeneReviews	RCV000014237	SCV002058094	not provided	Thrombophilia due to thrombin defect		no assertion provided	literature only	assoc with increased plasma levels of prothrombin
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV002468555	SCV002764637	established risk allele	Thrombophilia caused by F2 prothrombin deficiency		no assertion criteria provided	research	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.