rs1801711

Positions:

• chr1-169549811-C-T
• chr1-169549811-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP5_Strong BP4 BS1_Supporting

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
• Clinical Significance: drug response reviewed by expert panel P:17 U:1 B:1 O:5
• Conservation: PhyloP100: 3.48

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]

ACMG classification

Verdict is Uncertain_significance. 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_low_penetrance=1, risk_factor=1, Benign=1, drug_response=1, Pathogenic=13}. 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F5	NM_000130.5	c.1601G>A	p.Arg534Gln	missense_variant	10/25	ENST00000367797.9	NP_000121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F5	ENST00000367797.9	c.1601G>A	p.Arg534Gln	missense_variant	10/25	1	NM_000130.5	ENSP00000356771	P2
F5	ENST00000367796.3	c.1601G>A	p.Arg534Gln	missense_variant	10/25	5		ENSP00000356770	A2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2638 AN: 152200 Hom.: 37 Cov.: 32

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

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

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:17 Uncertain:1 Benign:1 Other:5

Revision: reviewed by expert panel

Submissions by phenotype

Thrombophilia due to activated protein C resistance Pathogenic:9 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Apr 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Established risk allele, no assertion criteria provided	research	Department 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 submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	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. -
Benign, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2006	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Variantyx, Inc.	Nov 04, 2022	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. -

Factor V deficiency Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2018	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] -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 13, 2017	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. -
risk factor, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2020	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 15, 2023	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2021

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 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2018

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. -

Thrombophilia due to activated protein C resistance;C4317320:Factor V deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UNC 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). -

Congenital factor V deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

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. -

Susceptibility to severe coronavirus disease (COVID-19) due to an impaired coagulation process Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jun 29, 2021

Differences 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 panel

curation

PharmGKB

Mar 24, 2021

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. Drug-variant association: Toxicity

Ischemic stroke Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 15, 2006

- -

Budd-Chiari syndrome, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 15, 2006

- -

Pregnancy loss, recurrent, susceptibility to, 1 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 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

Other links and lift over

dbSNP: rs6025; hg19: chr1-169519049;