ClinVar Genomic variation as it relates to human health
NM_000130.4(F5):c.1601G>A (p.Arg534Gln)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000130.4(F5):c.1601G>A (p.Arg534Gln)
Variation ID: 642 Accession: VCV000000642.124
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q24.2 1: 169549811 (GRCh38) [ NCBI UCSC ] 1: 169519049 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 3, 2017 Aug 25, 2024 Mar 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000130.5:c.1601G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000121.2:p.Arg534Gln missense NC_000001.11:g.169549811C>T NC_000001.10:g.169519049= NG_011806.1:g.41721G>A LRG_553:g.41721G>A LRG_553t1:c.1601G>A P12259:p.Arg534Gln - Protein change
- R534Q
- Other names
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F5, ARG506GLN
R506Q
F5:c.1601G>A (p.Arg534Gln)
factor V Leiden
- Canonical SPDI
- NC_000001.11:169549810:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 30x 0.00593
Trans-Omics for Precision Medicine (TOPMed) 0.01674
The Genome Aggregation Database (gnomAD) 0.01762
- Links
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ClinGen: CA114378 Genetic Testing Registry (GTR): GTR000019613 OMIM: 612309.0001 dbSNP: rs6025 Genetic Testing Registry (GTR): GTR000021482 Genetic Testing Registry (GTR): GTR000204879 Genetic Testing Registry (GTR): GTR000219927 Genetic Testing Registry (GTR): GTR000325434 Genetic Testing Registry (GTR): GTR000500035 Genetic Testing Registry (GTR): GTR000500304 Genetic Testing Registry (GTR): GTR000500323 Genetic Testing Registry (GTR): GTR000500421 Genetic Testing Registry (GTR): GTR000501123 Genetic Testing Registry (GTR): GTR000512436 Genetic Testing Registry (GTR): GTR000556798 Genetic Testing Registry (GTR): GTR000560790 Genetic Testing Registry (GTR): GTR000562175 Genetic Testing Registry (GTR): GTR000576393 Genetic Testing Registry (GTR): GTR000613302 UniProtKB: P12259#VAR_001213 VarSome
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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F5 | - | - |
GRCh38 GRCh37 |
1081 | 1104 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Budd-Chiari syndrome, susceptibility to
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risk factor (1) |
no assertion criteria provided
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Jun 15, 2006 | RCV000000676.12 |
risk factor (1) |
no assertion criteria provided
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Jun 15, 2006 | RCV000000675.13 | |
risk factor (1) |
no assertion criteria provided
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Jun 15, 2006 | RCV000023935.12 | |
Pathogenic; risk factor (3) |
criteria provided, multiple submitters, no conflicts
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Mar 4, 2020 | RCV000205002.29 | |
Pathogenic/Pathogenic, low penetrance (10) |
criteria provided, multiple submitters, no conflicts
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Jul 12, 2023 | RCV000454249.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2021 | RCV000616414.12 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001095681.10 | |
Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process
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Uncertain significance (1) |
no assertion criteria provided
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Jun 29, 2021 | RCV001806997.9 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2018 | RCV002399305.9 | |
hormonal contraceptives for systemic use response - Toxicity
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drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV003227589.9 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV003764502.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV003493407.2 | |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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drug response
Drug-variant association: Toxicity
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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hormonal contraceptives for systemic use response - Toxicity
Drug used for
Thrombosis
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV003925528.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Comment:
Drug is not necessarily used to treat response condition
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Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to activated protein C resistance
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538025.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
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 … (more)
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. (less)
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risk factor
(Mar 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor V deficiency
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271297.3
First in ClinVar: May 29, 2016 Last updated: Jul 06, 2020 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 9
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Pathogenic
(Apr 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to activated protein C resistance
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (UDN)
Accession: SCV001432487.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Clinical Features:
Nystagmus (present) , Palpitations (present) , Reduced ejection fraction (present) , Muscular hypotonia (present) , Muscle weakness (present) , Muscle spasm (present) , Infantile muscular … (more)
Nystagmus (present) , Palpitations (present) , Reduced ejection fraction (present) , Muscular hypotonia (present) , Muscle weakness (present) , Muscle spasm (present) , Infantile muscular hypotonia (present) , Renal tubular atrophy (present) , Mesangial abnormality (present) , Tubulointerstitial fibrosis (present) , Glomerulomegaly (present) , Podocyte foot process effacement (present) , Peripheral neuropathy (present) , Proteinuria (present) , Elevated serum creatine kinase (present) , Elevated plasma acylcarnitine levels (present) , Deep venous thrombosis (present) , Cellulitis (present) (less)
Age: 30-39 years
Sex: male
Ethnicity/Population group: Causasians
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to activated protein C resistance
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500857.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Comment:
GoldVariant submitter: Dr Karyn Mégy NIHR Bioresource - Cambridge University, UK
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Observation 1: Observation 2: Observation 3: Observation 4: Observation 5: Observation 6: Observation 7: |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to activated protein C resistance
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002519645.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243416.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
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Pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197848.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Oct 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor V deficiency
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839955.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Factor V deficiency
Thrombophilia due to activated protein C resistance
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251455.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
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Comment:
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 … (more)
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). (less)
Number of individuals with the variant: 2
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Pathogenic
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000728219.2
First in ClinVar: Apr 09, 2018 Last updated: Mar 22, 2021 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Aug 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor V deficiency
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001525756.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
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 … (more)
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] (less)
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Pathogenic, low penetrance
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Thrombophilia due to activated protein C resistance
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Variantyx, Inc.
Accession: SCV002754531.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 12, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Thrombophilia due to activated protein C resistance
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835241.2
First in ClinVar: Mar 11, 2023 Last updated: Oct 06, 2023 |
|
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital factor V deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000262346.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002706385.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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risk factor
(Jun 15, 2006)
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no assertion criteria provided
Method: literature only
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PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045226.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2019 |
Comment on evidence:
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina … (more)
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)
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|
Uncertain significance
(Jun 29, 2021)
|
no assertion criteria provided
Method: research
|
Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process
Affected status: yes
Allele origin:
germline
|
HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
Accession: SCV001750078.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Differences in coagulation-related proteins according to the genotype of patients with severe COVID-19
|
|
Pathogenic
(Jun 15, 2006)
|
no assertion criteria provided
Method: literature only
|
THROMBOPHILIA DUE TO FACTOR V LEIDEN
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020824.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2019 |
Comment on evidence:
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina … (more)
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)
|
|
risk factor
(Jun 15, 2006)
|
no assertion criteria provided
Method: literature only
|
STROKE, ISCHEMIC, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020825.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2019 |
Comment on evidence:
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina … (more)
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)
|
|
risk factor
(Jun 15, 2006)
|
no assertion criteria provided
Method: literature only
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BUDD-CHIARI SYNDROME, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020826.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2019 |
Comment on evidence:
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina … (more)
This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)
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Pathogenic
(Apr 05, 2022)
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no assertion criteria provided
Method: clinical testing
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Thrombophilia due to activated protein C resistance
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002583432.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Established risk allele
(-)
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no assertion criteria provided
Method: research
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Factor V Leiden thrombophilia
Affected status: unknown
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV002764636.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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. (less)
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Benign
(Mar 29, 2024)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Thrombophilia due to activated protein C resistance
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807713.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis. | Megy K | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 34355501 |
Risk prediction of developing venous thrombosis in combined oral contraceptive users. | McDaid A | PloS one | 2017 | PMID: 28750087 |
Diagnosis and management of factor V Leiden. | Campello E | Expert review of hematology | 2016 | PMID: 27797270 |
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation. | Banno F | Blood | 2015 | PMID: 26251307 |
Cerebrovascular Aneurysms May Be Associated with Thrombophilia-predisposing Mutations in Patients with Familial Risk. | Andreou A | In vivo (Athens, Greece) | 2015 | PMID: 25977387 |
Primary Budd-Chiari syndrome in a 3-year-old boy with homozygous factor V Leiden G1691A mutation. | Boskovic A | European journal of pediatrics | 2014 | PMID: 23677252 |
Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. | Simone B | European journal of epidemiology | 2013 | PMID: 23900608 |
Risk of venous thromboembolism and myocardial infarction associated with factor V Leiden and prothrombin mutations and blood type. | Sode BF | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2013 | PMID: 23382263 |
Thrombomodulin-dependent effect of factor V Leiden mutation on the cross-linking of α2-plasmin inhibitor to fibrin and its consequences on fibrinolysis. | Koncz Z | Thrombosis research | 2012 | PMID: 22704462 |
Thrombomodulin-dependent effect of factor VLeiden mutation on factor XIII activation. | Koncz Z | Thrombosis research | 2012 | PMID: 21774968 |
Factor V Leiden thrombophilia. | Kujovich JL | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21116184 |
The R306G and R506Q mutations in coagulation Factor V reveals additional cleavage sites for Activated Protein C in the R313-R321 region and at R505. | Dirven RJ | Thrombosis research | 2010 | PMID: 20051284 |
The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. | Gohil R | Thrombosis and haemostasis | 2009 | PMID: 19652888 |
Phenotypic Heterogeneity in Patients with Homozygous Prothrombin 20210AA Genotype. A paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. | Bosler D | The Journal of molecular diagnostics : JMD | 2006 | PMID: 16931580 |
Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke. | Martinelli I | Haematologica | 2006 | PMID: 16769590 |
Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. | Zivelin A | Blood | 2006 | PMID: 16493002 |
Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. | Slooter AJ | Journal of thrombosis and haemostasis : JTH | 2005 | PMID: 15946211 |
R255h amino acid substitution of protein Z identified in patients with factor V Leiden mutation. | Kemkes-Matthes B | British journal of haematology | 2005 | PMID: 15638861 |
Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. | Casas JP | Archives of neurology | 2004 | PMID: 15534175 |
Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. | Sidney S | Contraception | 2004 | PMID: 15208046 |
Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. | Juul K | Annals of internal medicine | 2004 | PMID: 14996674 |
Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. | Press RD | Archives of pathology & laboratory medicine | 2002 | PMID: 12421138 |
Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. | Juul K | Blood | 2002 | PMID: 12070000 |
Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use. | Legnani C | European heart journal | 2002 | PMID: 12069454 |
Improved hemoglobin status and reduced menstrual blood loss among female carriers of factor V Leiden--an evolutionary advantage? | Lindqvist PG | Thrombosis and haemostasis | 2001 | PMID: 11686338 |
Spontaneous thrombosis in mice carrying the factor V Leiden mutation. | Cui J | Blood | 2000 | PMID: 11110695 |
Mutations in coagulation factors in women with unexplained late fetal loss. | Martinelli I | The New England journal of medicine | 2000 | PMID: 11018168 |
Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. | Gerhardt A | The New England journal of medicine | 2000 | PMID: 10666427 |
Double-homozygosity for factor V Leiden and the prothrombin gene G20210A variant in a young patient with idiopathic venous thrombosis. | Mainardi JR | Blood | 1999 | PMID: 10507841 |
Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford. | Zehnder JL | Thrombosis and haemostasis | 1999 | PMID: 10494770 |
The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. | De Stefano V | The New England journal of medicine | 1999 | PMID: 10477778 |
Simultaneous genotyping for factor V Leiden and prothrombin G20210A variant by a multiplex PCR-SSCP assay on whole blood. | Meyer M | Thrombosis and haemostasis | 1999 | PMID: 10348711 |
Homozygous factor V Leiden mutation in a child with Budd-Chiari syndrome. | Gürakan F | Journal of pediatric gastroenterology and nutrition | 1999 | PMID: 10328130 |
Budd-Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis. | Leebeek FW | British journal of haematology | 1998 | PMID: 9734642 |
Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group. | de Bruijn SF | BMJ (Clinical research ed.) | 1998 | PMID: 9518910 |
Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss--a possible evolutionary selection mechanism. | Lindqvist PG | Thrombosis and haemostasis | 1998 | PMID: 9459326 |
A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. | Chan WP | Blood | 1998 | PMID: 9454741 |
Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations. | Gregg JP | American journal of medical genetics | 1997 | PMID: 9415695 |
Retinal arterial occlusion in a child with factor V Leiden and thermolabile methylene tetrahydrofolate reductase mutations. | Talmon T | American journal of ophthalmology | 1997 | PMID: 9372726 |
The prevalence of factor V Leiden (1691 G-->A) mutation in Turkey. | Gürgey A | The Turkish journal of pediatrics | 1997 | PMID: 9339109 |
Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis. | Mahmoud AE | Gut | 1997 | PMID: 9245936 |
Inherited prethrombotic disorders and infectious purpura. | Westendorp RG | Thrombosis and haemostasis | 1996 | PMID: 8822583 |
HELLP syndrome associated with factor V R506Q mutation. | Brenner B | British journal of haematology | 1996 | PMID: 8616100 |
Population study of the G1691A mutation (R506Q, FV Leiden) in the human factor V gene that is associated with resistance to activated protein C. | Braun A | Human genetics | 1996 | PMID: 8566967 |
Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. | Ridker PM | The New England journal of medicine | 1995 | PMID: 7877648 |
Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. | Ridker PM | Circulation | 1995 | PMID: 7586244 |
Mutation in blood coagulation factor V associated with resistance to activated protein C. | Bertina RM | Nature | 1994 | PMID: 8164741 |
Human genetics. Bad blood by mutation. | Majerus PW | Nature | 1994 | PMID: 8164730 |
Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. | Koeleman BP | Blood | 1994 | PMID: 8049422 |
Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. | Vandenbroucke JP | Lancet (London, England) | 1994 | PMID: 7968118 |
Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. | Voorberg J | Lancet (London, England) | 1994 | PMID: 7911872 |
Activated protein C resistance caused by Arg506Gln mutation in factor Va. | Greengard JS | Lancet (London, England) | 1994 | PMID: 7910348 |
High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis. | Beauchamp NJ | British journal of haematology | 1994 | PMID: 7803250 |
https://www.pharmgkb.org/clinicalAnnotation/1183689558 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166153554 | - | - | - | - |
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Text-mined citations for rs6025 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.