Important Variant Information for F5

Submitted by: Jennifer Bushwitz, Michael A. Pacanowski, and Julie A. Johnson (PEAR)
Reviewed by: Under Review
Submitted date: October 11, 2006

There is One Important Variant for F5.

F5:1691G>A (nucleotide reference based on F5 sequence published by Jenny et al. [PMID: 3110773]
( Factor V Leiden (FVL) )
( Arg506Gln (amino acid position not including leader peptide (28 amino acids)). )

Gene HGNC Name:	F5
Variant Summary:	The Factor V Leiden (FVL, 1691G>A) polymorphism results in an Arg to Gln substitution at position 506 in the Factor V heavy chain. Factor V has a 28 amino acid leader peptide, thus this polymorphism has also been referred to as Arg534Gln in the literature and some databases [PMID: 3110773]. This amino acid substitution occurs at an important cleavage site and significantly reduces the rate at which factor Va is deactivated by activated protein C (APC). FVL also decreases the APC cofactor activity of factor V in the deactivation of factor VIIIa. The combination of impaired factor Va and VIIIa deactivation results in a prothrombotic state. [PMID 7657663, 7989361, 7876154, 8815575, 15257017, 10194434, 8573079, 16359508, 14976057, 12881304] The minor allele frequency of FVL reported in HapMap, dbSNP, and other databases is between 0.8%-2.7% in European populations. However, reports in the primary literature show great variability in allele frequency according geographic distribution. FVL is found predominantly in individuals of European descent. Reported allele frequencies are as high as 15% in some areas, with the greatest prevalence in the Eastern Mediterranean and Sweden. FVL is very rare among populations of African, East Asian and Native American descent with reported allele frequencies <1%. In admixed populations (i.e. Hispanic), allele frequencies in some areas are consistent with that of the Europeans. [PMID: 16651467, 9109469, 9157591, 11259157, 10936863, 9271712, 9415695, 7475606] The association between FVL and venous thromboembolism (VTE) is well established. Heterozygotes have at least a two-fold greater risk of deep vein thrombosis, and the risk appears to be additive as the estimates are much higher in homozygotes. [PMID: 16651467, 9382368, 7877648, 11529695, 7888671, 10073951, 14996674, 12368166, 16606808] FVL enhances the risk of VTE associated with the use of oral contraceptives and estrogen hormone replacement therapy. Mechanistically, FVL enhances APC resistance induced by oral contraceptives and hormone replacement therapy. [PMID: 12869355, 14551147, 12138364, 11703344] Users of oral contraceptives with the FVL mutation have up to a 40-fold increased risk of VTE compared to nonusers without the variant, although the risk estimates vary across studies given the low frequency of exposed cases with the variant. In a meta-analysis of six studies, the pooled odds of VTE with oral contraceptives in FVL carriers was 15.62 (95% confidence interval 8.66-28.15), which is substantially higher than the population risk estimates (odds ratio for VTE in all users versus nonusers 3.10 [95% confidence interval 2.17-4.42]). Similarly, individuals receiving oral estrogen hormone replacement therapy with FVL have as much as a 25-fold increased risk of VTE compared to nonusers without the mutation. Transdermal preparations may not carry the same risk. [PMID: 9459317, 10943572, 10073976 , 11532625, 7968118, 15467059, 16301339, 16113779, 12069454, 12067913, 11886391] Despite these high relative risks, the absolute risks remain low and so testing for FVL is not recommended for all potential oral contraceptive or hormone replacement therapy users, although these should be avoided in women known to be a carrier of FVL. [16595080] FVL does not appear to modify the risk for venous thromboembolism among women with breast cancer receiving tamoxifen [PMID: 14512389, 16818854]. Most studies failed to show an association between FVL and arterial thrombosis in the general population. However, a recent meta-analysis of 60 studies, which included over 15,000 cases, demonstrated a significantly greater risk of coronary disease and myocardial infarction in FVL carriers. [PMID: 9531249, 8553401, 8581514, 10195931, 10702702, 11406725, 16503463, 7877648, 10666427, 15534175, 14660985, 15947254, 12877676, 9108400, 14574075]. Additionally, the risk of stroke and myocardial infarction is increased in female carriers of FVL that smoke. [PMID: 15947254, 12877676, 9108400] Anticoagulation therapy is not currently recommended for individuals with FVL who have no history of thromboembolism. [PMID: 12368166, 11958494, 12008938, 16595080, 9462312, 16173967, 11127850] In animal models, heterozygosity for FVL confers a survival benefit in severe sepsis. [PMID: 12869495, 15118524] However, human studies suggest that FVL heterozygotes have similar outcomes in the setting of sepsis and derive similar benefits and adverse events from drotrecogin alfa (recombinant human activated protein C) as noncarriers. [PMID: 16444434, 15118525]
Key PubMed IDs:	2827731 3110773 3220473 7475606 7657663 7876154 7877648 7888671 7968118 7989361 8164741 8553401 8573079 8581514 8815575 9108400 9109469 9157591 9207293 9245936 9271712 9382368 9415695 9459317 9462312 9531249 9878639 10073951 10073976 10194434 10195931 10666427 10702702 10936863 10943572 11127850 11259157 11406725 11435304 11529695 11532625 11703344 11859850 11886391 11950687 11958494 12008938 12067913 12069454 12070000 12138364 12368166 12869355 12869495 12877676 12881304 14551147 14617013 14660985 14976057 14996674 15118524 15118525 15257017 15467059 15534175 15947254 16113779 16173967 16301339 16359508 16444434 16503463 16595080 16606808 16651467 14574075 14512389 16818854
Genomic Variant & GenBank ID:	T>C 20009404 on NT_004487
mRNA Variant & GenBank ID:	G>A 1746 on NM_000130(nucleotide position relative to start of 5'UTR) G>A 1691 on M16967.1
Protein Variant & GenBank ID:	Arg>Gln 534 on NP_000121 (amino acid position including leader peptide [28 amino acids])
dbSNP rs#:	rs6025
dSNP ss#:	ss7639
GoldenPath Position:	chr1:167785673;(hg18)
Drugs/Substrates:	Oral contraceptives: 12069454, 11859850, 16301339, 16113779, 15467059, 14551147, 12869355, 12138364, 7968118, 9459317, 10943572, 10073976, 11532625 Estrogens: 12069454, 11859850, 16301339, 16113779, 15467059, 14551147, 12869355, 12138364, 11703344, 7968118, 9459317, 10943572, 10073976, 11532625, 12067913, 11886391 Tamoxifen: 14512389, 16818854 Drotrecogin alfa: 15118525
Phenotypes/Diseases:	Venous thromboembolism: 16651467, 9382368, 7877648, 11529695, 7888671, 10073951, 14996674, 12368166, 16606808, 12069454, 10666427 Thrombosis (arterial): 9531249, 8553401, 8581514, 10195931, 10702702, 11406725, 16503463, 7877648, 10666427, 15534175, 14660985, 15947254, 12877676, 9108400, 14574075 Sepsis: 15118525, 16444434
Coriell Clone containing heterozygous reference allele:	GM16028
Coriell Clone containing homozygous minor allele:	GM14899

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