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rs60031897

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PP5_StrongBP4BS1_SupportingBS2

The NM_000130.5(F5):c.1601G>A(p.Arg534Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,166 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.017 ( 37 hom., cov: 32)
Exomes 𝑓: 0.022 ( 413 hom. )

Consequence

F5
NM_000130.5 missense

Scores

3
3

Clinical Significance

drug response reviewed by expert panel P:16U:1B:1O:5

Conservation

PhyloP100: 3.48
Variant links:
Genes affected
F5 (HGNC:3542): (coagulation factor V) This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. [provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP5
Variant 1-169549811-C-T is Pathogenic according to our data. Variant chr1-169549811-C-T is described in ClinVar as [drug_response]. Clinvar id is 642.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=12, risk_factor=1, Benign=1, Pathogenic_low_penetrance=1, drug_response=1}. Variant chr1-169549811-C-T is described in Lovd as [Pathogenic]. Variant chr1-169549811-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.007941633).. Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2635/152318) while in subpopulation NFE AF= 0.0263 (1787/68026). AF 95% confidence interval is 0.0253. There are 37 homozygotes in gnomad4. There are 1248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 37 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F5NM_000130.5 linkuse as main transcriptc.1601G>A p.Arg534Gln missense_variant 10/25 ENST00000367797.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F5ENST00000367797.9 linkuse as main transcriptc.1601G>A p.Arg534Gln missense_variant 10/251 NM_000130.5 P2
F5ENST00000367796.3 linkuse as main transcriptc.1601G>A p.Arg534Gln missense_variant 10/255 A2

Frequencies

GnomAD3 genomes
AF:
0.0173
AC:
2638
AN:
152200
Hom.:
37
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00446
Gnomad AMI
AF:
0.0932
Gnomad AMR
AF:
0.00929
Gnomad ASJ
AF:
0.0199
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0126
Gnomad FIN
AF:
0.0234
Gnomad MID
AF:
0.0601
Gnomad NFE
AF:
0.0263
Gnomad OTH
AF:
0.0201
GnomAD4 exome
AF:
0.0219
AC:
31939
AN:
1460848
Hom.:
413
Cov.:
31
AF XY:
0.0218
AC XY:
15857
AN XY:
726812
show subpopulations
Gnomad4 AFR exome
AF:
0.00290
Gnomad4 AMR exome
AF:
0.00711
Gnomad4 ASJ exome
AF:
0.0191
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0140
Gnomad4 FIN exome
AF:
0.0212
Gnomad4 NFE exome
AF:
0.0246
Gnomad4 OTH exome
AF:
0.0182
GnomAD4 genome
AF:
0.0173
AC:
2635
AN:
152318
Hom.:
37
Cov.:
32
AF XY:
0.0168
AC XY:
1248
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00445
Gnomad4 AMR
AF:
0.00928
Gnomad4 ASJ
AF:
0.0199
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0122
Gnomad4 FIN
AF:
0.0234
Gnomad4 NFE
AF:
0.0263
Gnomad4 OTH
AF:
0.0199
Alfa
AF:
0.0224
Hom.:
48
Bravo
AF:
0.0167

ClinVar

Significance: drug response
Submissions summary: Pathogenic:16Uncertain:1Benign:1Other:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Thrombophilia due to activated protein C resistance Pathogenic:9Benign:1
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHApr 08, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 15, 2006- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 30, 2016The 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. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 12, 2023- -
Established risk allele, no assertion criteria providedresearchDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinApr 05, 2022- -
Pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Pathogenic, low penetrance, criteria provided, single submitterclinical testingVariantyx, Inc.Nov 04, 2022This 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. -
Factor V deficiency Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 24, 2018This 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] -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 13, 2017This 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. -
risk factor, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 04, 2020F5 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. -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 22, 2021Commonly 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 -
Thrombophilia due to activated protein C resistance;C4317320:Factor V deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-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). -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2018The 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. -
Congenital factor V deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasJun 29, 2021Differences in coagulation-related proteins according to the genotype of patients with severe COVID-19 -
hormonal contraceptives for systemic use response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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. Drug-variant association: Toxicity
Ischemic stroke Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 15, 2006- -
Budd-Chiari syndrome, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 15, 2006- -
Pregnancy loss, recurrent, susceptibility to, 1 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 15, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_noAF
Uncertain
0.040
Cadd
Pathogenic
28
DEOGEN2
Benign
0.31
T;T
LIST_S2
Uncertain
0.87
D;D
MetaRNN
Benign
0.0079
T;T
Sift4G
Uncertain
0.014
D;D
Vest4
0.20
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6025; hg19: chr1-169519049; API