ClinVar Miner

Submissions for variant NM_000130.4(F5):c.1601G>A (p.Arg534Gln) (rs6025)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205002 SCV000262346 pathogenic Factor V deficiency 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 534 of the F5 protein (p.Arg534Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant, also known as the Factor V Leiden mutation, is a well documented and common cause of activated protein C resistance (PMID: 8164741, 7910348). This variant has also been reported as R506Q. ClinVar contains an entry for this variant (Variation ID: 642). This variant disrupts the activated protein C cleavage site in the F5 protein and leads to a defective anticoagulant response in vitro (PMID: 7911872, 7910348). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000205002 SCV000271297 risk factor Factor V deficiency 2020-03-04 criteria provided, single submitter clinical testing F5 c.1601G>A (p.Arg534Gln; commonly known as Factor V Leiden, historically reported as p.Arg506Gln) has been associated with increased risk for venous thromboembolism (VTE). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (2.96%, Genome Aggregation Database (gnomAD); rs6025) and is present in ClinVar (ID: 642). Several meta-analyses and case-control studies have reported odds ratios between 2.2-4.93 for developing VTE in heterozygous carriers (OR=2.2 [95% CI 2.0-2.5] Sode 2013, OR=4.22 [95% CI 3.35-5.32] Simone 2013, OR=4.93 [95% CI 4.41-5.52] Gohil 2009, OR= 2.4 [95% CI 1.3–3.8] Juul 2004) and odds ratios between 7-11.5 for developing VTE in homozygous carriers (OR=7.0 [95% CI 4.8-10] Sode 2013, OR=11.45 [95% CI 6.79-19.29] Simone 2013). In vivo and in vitro functional studies provide evidence that the Factor V Leiden variant impacts protein function (Dirven 2010, Cui 2000, Banno 2015, Koncz 2012). In summary, the p.Arg534Gln variant meets criteria for classification as an established risk allele for VTE.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454249 SCV000538025 pathogenic Thrombophilia due to activated protein C resistance 2016-03-30 criteria provided, single submitter clinical testing The c.1601G>A (p.Arg534Gln) missense variant is a common disease-causing variant in the F5 gene. This missense variant destroys one of three APC cleavage sites in factor V, rendering the protein resistant to APC inactivation. Arg534Gln heterozygotes and homozygotes have an increased risk for Factor V Thrombophilia; however, clinical expression is variable and most individuals never develop thrombosis (GeneReviews: Kujovich et al., 2010, http://www.ncbi.nlm.nih.gov/books/NBK1368/). Therefore, this collective evidence supports the classification of the c.1601G>A (p.Arg534Gln) as a Pathogenic variant for Factor V Thrombophilia.
GeneDx RCV000616414 SCV000728219 benign not specified 2018-02-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000205002 SCV000839955 pathogenic Factor V deficiency 2017-10-13 criteria provided, single submitter clinical testing This c.1601G>A (p.Arg534Gln) variant is known as the Factor V Leiden variant (legacy name p.Arg506Gln). Factor V Leiden variant is associated with thrombophilia due to activated protein C resistance [MIM:188055]. Studies suggest that the relative risk for venous thrombosis associated with the factor V Leiden variant in the absence of other acquired or environmental predispositions is approximately 4- to 7-fold for heterozygotes and 80-fold for homozygotes (PMID 16024978). This variant is classified as pathogenic. Homozygosity for this variant is also considered medically actionable.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV001095681 SCV001251455 pathogenic Factor V deficiency; Thrombophilia due to activated protein C resistance criteria provided, single submitter research Factor V Leiden variant (F5 c.1601G>A (p.R534Q)) is associated with an increased risk of blood clotting (thrombophilia). Factor V Leiden is the most common inherited form of thrombophilia. Individuals homozygous for Factor V Leiden have an estimated 40 to 80 fold increased risk of venous thrombosis compared to individuals without Factor V Leiden (PMID: 12421138; 16931580).
OMIM RCV000000674 SCV000020824 pathogenic Thrombophilia due to factor V Leiden 2006-06-15 no assertion criteria provided literature only
OMIM RCV000000675 SCV000020825 risk factor Ischemic stroke, susceptibility to 2006-06-15 no assertion criteria provided literature only
OMIM RCV000000676 SCV000020826 risk factor Budd-Chiari syndrome, susceptibility to 2006-06-15 no assertion criteria provided literature only
OMIM RCV000023935 SCV000045226 risk factor Recurrent abortion 2006-06-15 no assertion criteria provided literature only

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