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

gnomAD frequency: 0.01762  dbSNP: rs6025

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV003227589	SCV003925528	drug response	hormonal contraceptives for systemic use response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Invitae	RCV003764502	SCV000262346	pathogenic	Congenital factor V deficiency	2024-01-31	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 is present in population databases (no rsID available, gnomAD 3.0%), and has an allele count higher than expected for a pathogenic variant. 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). ClinVar contains an entry for this variant (Variation ID: 642). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects F5 function (PMID: 7910348, 7911872). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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	pathogenic	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Commonly referred to as factor V Leiden and previously known as p.Arg506Gln; c.1691G>A using historical nomenclature Factor V Leiden is found in 90–95% of all patients with APC resistance (Bertina et al., 1994; Voorberg et al., 1994; Zhang et al., 2018) The presence of the factor V Leiden variant in the heterozygous and homozygous state has been reported in association with an increased risk for venous thrombosis (Zhang et al., 2018) Heterozygosity for this variant is associated with a 4-8 fold increased risk for venous thrombosis (Rosendaal et al., 1995; Zoller et al., 1997; Zhang et al., 2018) Homozygosity for this variant is associated with up to an 80-fold increased risk for venous thrombosis (Rosendaal et al., 1995; Zhang et al., 2018) Published studies demonstrate a deleterious effect on protein function (Nicolaes et al., 1995; Pezeshkpoor et al., 2016) This test cannot definitively predict the occurrence or recurrence of a thrombotic event in an individual with this variant
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).
Undiagnosed Diseases Network, NIH	RCV000454249	SCV001432487	pathogenic	Thrombophilia due to activated protein C resistance	2020-04-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000205002	SCV001525756	pathogenic	Factor V deficiency	2018-08-24	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been known as the Factor V Leiden variant [PMID 8164741, 26990548, 25977387, 26251307, 23677252, Factor V Leiden]
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000454249	SCV002500857	pathogenic	Thrombophilia due to activated protein C resistance		criteria provided, single submitter	clinical testing
Mendelics	RCV000454249	SCV002519645	pathogenic	Thrombophilia due to activated protein C resistance	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399305	SCV002706385	pathogenic	Inborn genetic diseases	2018-01-23	criteria provided, single submitter	clinical testing	The p.R534Q pathogenic mutation (also known as c.1601G>A, R506Q, 1691G>A, and factor V Leiden), located in coding exon 10 of the F5 gene, results from a G to A substitution at nucleotide position 1601. The arginine at codon 534 is replaced by glutamine, an amino acid with highly similar properties. This mutation abolishes one of the three activated protein C (APC) cleavage sites; APC is an anticoagulant, which regulates the coagulation cascade by degrading activated factor V. Heterozygosity for the factor V Leiden (FVL) allele is associated with a 3-8 fold increased risk for venous thrombosis (Campello E et al. Expert Rev Hematol. 2016;9(12):1139-49). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Variantyx, Inc.	RCV000454249	SCV002754531	pathogenic, low penetrance	Thrombophilia due to activated protein C resistance	2022-11-04	criteria provided, single submitter	clinical testing	This is a nonsynonymous variant in the F5 gene (OMIM 612309). Pathogenic variants in this gene have been associated with factor V Leiden thrombophilia. This variant, also known as factor V Leiden or p.Arg506Gln, is associated with an increased risk for venous thromboembolism (VTE) due to activated protein C resistance. The frequency of this variant in affected individuals is significantly increased compared to controls and studies have shown that heterozygous carriers are at increased risk for VTE (OR = 4.38, 95% CI: 3.48-5.51, PMID: 23900608), while homozygous individuals are at an even greater risk and tend to develop thrombosis at a younger age (OR = 9.45 95% CI: 6.72-13.30, PMID: 19652888; OR = 11.45 95% CI: 6.79-19.29, PMID: 23900608) (PS4). Functional studies have shown that this variant alters factor V protein function (PMID: 11110695, 20051284, 22704462, 26251307) (PS3). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant has a 2.627% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic with reduced penetrance.
Baylor Genetics	RCV000454249	SCV003835241	pathogenic	Thrombophilia due to activated protein C resistance	2023-07-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493407	SCV004243416	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000454249	SCV004807713	benign	Thrombophilia due to activated protein C resistance	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000454249	SCV000020824	pathogenic	Thrombophilia due to activated protein C resistance	2006-06-15	no assertion criteria provided	literature only
OMIM	RCV000000675	SCV000020825	risk factor	Ischemic stroke	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	Pregnancy loss, recurrent, susceptibility to, 1	2006-06-15	no assertion criteria provided	literature only
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas	RCV001806997	SCV001750078	uncertain significance	Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process	2021-06-29	no assertion criteria provided	research	Differences in coagulation-related proteins according to the genotype of patients with severe COVID-19
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000454249	SCV002583432	pathogenic	Thrombophilia due to activated protein C resistance	2022-04-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000454249	SCV002764636	established risk allele	Thrombophilia due to activated protein C resistance		no assertion criteria provided	research	The F5 c.1601A>G (p.Arg534Gln) variant is commonly known as the Factor V Leiden variant, and is known to cause an increased risk of venous thromboembolism (VTE). The reported risk of venous thromboembolism (VTE) is increased 3-8 fold in heterozygotes, and is increased 9-80 fold in homozygotes. The Leiden variant also results in an increased risk of pregnancy-related VTE and an increased risk of cerebral venous thrombosis in children (Kujovich_1999_PMID:20301542). The variant was identified in dbSNP (ID: rs6025) and ClinVar (classified as pathogenic by Invitae, Knight Diagnostic Laboratories and Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine, as benign by GeneDx and as a risk factor by Laboratory for Molecular Medicine). The variant was identified in control databases in 2511 of 143302 chromosomes (31 homozygous) at a frequency of 0.01752 (Genome Aggregation Database March 6, 2019, v3). The variant was observed in the following populations: Amish in 77 of 900 chromosomes (freq: 0.08556), European (non-Finnish) in 1724 of 64578 chromosomes (freq: 0.0267), European (Finnish) in 250 of 10472 chromosomes (freq: 0.02387), Ashkenazi Jewish in 70 of 3324 chromosomes (freq: 0.02106), South Asian in 40 of 3052 chromosomes (freq: 0.01311), Other in 23 of 2152 chromosomes (freq: 0.01069), Latino in 131 of 13662 chromosomes (freq: 0.009589), and African in 196 of 42032 chromosomes (freq: 0.004663), but was not observed in the East Asian population. The p.Arg534 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant is located in one of three activated protein C (APC) cleavage sites in the factor V protein; functional analysis of this variant has demonstrated resistant to APC cleavage leading to a poor anticoagulant response (Balinda_1994_PMID:8164741; Kujovich_1999_PMID:20301542). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.