The F5 NM_000130.5:c.1601G>A (NP_000121.2:p.(Arg534Gln)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: The Factor V Leiden allele slows activated-protein-C inactivation approximately tenfold and produces increased thrombin generation, but primary assay controls are not fully available. Based on available guidelines, this variant is considered to be Benign. This variant is considered to be drug response by the VCEP (ClinPGx; ClinVar ID 642).
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.F5 encodes coagulation factor V, a blood protein that helps activate thrombin and form clots. Changes in this gene can cause either a rare inherited bleeding disorder or activated protein C resistance, an inherited tendency toward excessive blood clotting. F5 is not established as a cancer-associated gene.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: the Factor V Leiden allele slows activated-protein-C inactivation approximately tenfold and produces increased thrombin generation, but primary assay controls are not fully available.
Met, stand-alone: the Amish gnomAD v4.1 AF is 9.32018%, exceeding the generic BA1 threshold of 5%.
Met, strong: gnomAD v4.1 total AF is 2.14324%, exceeding the generic BS1 threshold of 1% and occurring across several populations.
Benign: BA1 stand-alone is met by the Amish allele frequency above 5%; BS1 is also strong, while PS3 supporting does not satisfy a pathogenic rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 34,574 / 1,613,166 alleles. Recorded AF 0.0214324. Recorded homozygote count 450.
Absent from gnomAD v2.1.
This variant is present in gnomAD-Canada v1.0 (AF= 0.021555000542947116, 397/18418 alleles, homozygotes = 7).
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
22 Pathogenic · 1 risk factor · 1 Pathogenic, low penetrance · 1 Benign. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers F5, so the generic ACMG/AMP rules supplied for this interpretation govern.
The exact variant is NM_000130.5:c.1601G>A, p.Arg534Gln; literature frequently retrieved for Factor V Leiden p.Arg506Gln/c.1691G>A is a different variant and was not transferred.
PP5 and BP6 were restricted to exact-variant expert-panel classifications as required; the only expert-panel classification is drug response.
No criteria match.
PS3 is met at supporting strength. The case variant is the Factor V Leiden rs6025 allele, represented here as NM_000130.5:c.1601G>A (p.Arg534Gln) and described in the reviewed source under historical numbering as c.1691G>A (p.Arg506Gln). The source summarizes biologically relevant functional evidence: activated protein C normally cleaves Factor Va at Arg306, Arg506, and Arg679, whereas the variant at the Arg506 cleavage site makes Factor Va resistant to activated protein C and slows inactivation approximately tenfold, producing increased thrombin generation. It also describes the activated-protein-C resistance assay, including normal-plasma comparison and modified Factor V-deficient-plasma testing, with sensitivity and specificity approaching 100% for Factor V Leiden. This supports a damaging effect in vivo and in vitro, but the available record is a review summary rather than a primary assay report with complete controls and reproducibility data; therefore strong PS3 is not assigned.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BA1 is met at stand-alone strength. The generic ACMG/AMP threshold is an allele frequency of at least 5%; although the gnomAD v4.1 all-comers AF is 0.0214324 (2.14324%), the variant reaches AF 0.0932018 (9.32018%; 85/912 alleles) in the Amish population, exceeding the 5% threshold. The gnomAD v2.1 exome result is absent, but gnomAD v4.1 supplies the observed ancestry-specific frequency used here.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is met at strong strength under the generic default. The variant's gnomAD v4.1 total AF is 0.0214324 (2.14324%), exceeding the supplied generic SVI default of 1% for BS1; the frequency is also elevated across multiple populations, including European non-Finnish AF 0.0247183 and South Asian AF 0.0139456, rather than being confined to one ancestry. The available evidence does not provide a validated disease prevalence, penetrance, or allelic-heterogeneity-based maximum credible allele-frequency calculation for this specific F5 disorder, so the generic default is applied with that limitation noted; the 2.14% overall frequency is nevertheless above the stated generic threshold.
Allele frequency is greater than expected for the disorder.
No VCEP covers F5, and vcep_materials.json has no domain_tables entry for F5. The case hotspot assessment explicitly states that the variant does not lie in a statistically significant hotspot, and the reviewed evidence does not establish that residue 534 lies in a critical and well-established functional domain without benign variation. Therefore neither PM1 path is supported.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met. Although the variant is absent from gnomAD v2.1 exomes, it is present at a clearly non-extremely-low frequency in gnomAD v4.1: total AF 0.0214324 (2.14324%), with 34,574 alternate alleles and 450 homozygotes. This exceeds the supplied generic PM2 supporting threshold of <=0.0001 by more than two orders of magnitude, so the newer all-comers population evidence precludes PM2.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is a missense SNV, so PP3 is evaluated through the REVEL path only. The governing generic threshold for PP3 supporting is REVEL >= 0.644, but no REVEL score is available for NM_000130.5:c.1601G>A (p.Arg534Gln); therefore PP3 is not met. The available SpliceAI result is not used because splice prediction is not the governing path for a missense variant.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The governing rule is ACMG/AMP PP5: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The exact variant has many single-laboratory or ordinary ClinVar Pathogenic submissions, but no exact-variant ClinVar expert-panel classification as Pathogenic or Likely pathogenic. The sole exact-variant expert-panel record is ClinPGx's drug-response classification, which is not Pathogenic or Likely pathogenic and does not satisfy PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. No well-established functional study in the reviewed evidence shows that this Factor V Leiden allele has no damaging effect on protein function or splicing. Instead, the available functional evidence describes resistance to activated protein C, slower Factor Va inactivation, and increased thrombin generation, which is inconsistent with a no-damaging-effect conclusion. The available evidence concerns a missense substitution, so splicing is not the relevant negative-functional endpoint here.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense SNV, so BP4 is evaluated through the REVEL path only. The governing generic threshold for BP4 supporting is REVEL <= 0.29, but no REVEL score is available for NM_000130.5:c.1601G>A (p.Arg534Gln); therefore BP4 is not met. The available SpliceAI result is not used because splice prediction is not the governing path for a missense variant.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The governing rule is ACMG/AMP BP6: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The exact variant has one ordinary/flagged single-laboratory Benign submission, but no exact-variant ClinVar expert-panel classification as Benign or Likely benign. Under the specified generic rule, that non-expert assertion cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_000121.2:p.(Arg534Gln), but the reviewed literature reports the classic F5 Leiden change as p.Arg506Gln and does not document a previously established pathogenic variant with the same amino-acid substitution caused by a different nucleotide change. ClinVar records this exact variant, which is not sufficient for PS1 because PS1 requires a prior pathogenic variant with the same amino-acid change regardless of nucleotide change. No verified alternate-nucleotide p.Arg534Gln comparator was identified.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No proband-level clinical pedigree or parental testing evidence is documented for NM_000130.5:c.1601G>A (p.Arg534Gln). Specifically, the available evidence does not establish that the variant is de novo, does not confirm both maternity and paternity, and does not document disease in the proband or absence of a family history. Therefore, PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing rule is ACMG/AMP PS4: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." Note 1 requires an RR or OR >5.0 with a confidence interval that does not include 1.0. The literature_pass ai_classified_papers lead (PMID:23382263) was verified against its full-text extraction, but it studied the different F5 p.Arg506Gln/c.1691G>A Factor V Leiden variant, not this exact c.1601G>A/p.Arg534Gln variant; its reported hazard ratios therefore cannot be transferred. Other extracted case-control or meta-analysis papers likewise studied Factor V Leiden or other variants and did not provide affected-versus-control counts for this exact variant. gnomAD v4.1 shows the exact variant at AF 0.0214324 (34,574/1,613,166 alleles), but no affected-case frequency is available, so an exact-variant OR and 95% CI cannot be calculated. The PS4 threshold cannot therefore be evaluated for this variant.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed from the available evidence. No affected-proband observation documents NM_000130.5:c.1601G>A with a pathogenic F5 allele in trans, and no parental or offspring testing establishes phase. The available ClinVar and literature records do not provide a verified compound-heterozygous or recessive factor V deficiency observation for this specific variant.
PM3: For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
The reviewed case evidence does not identify a different missense change at the same amino-acid residue 534 that has been determined pathogenic. The PM5 candidate file contains zero candidates and explicitly states that classic same-residue PM5 semantics could not be confirmed; the reviewed Factor V Leiden papers concern the same known change under alternate historical numbering, not a different missense substitution at the residue.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No proband-level clinical pedigree or parental testing evidence is documented for NM_000130.5:c.1601G>A (p.Arg534Gln). The available evidence does not establish an assumed de novo occurrence and does not provide the parental testing information needed to distinguish PM6 from PS2. Therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No family segregation study is documented for NM_000130.5:c.1601G>A (p.Arg534Gln). The available records do not identify multiple affected family members, their genotypes, phenotype consistency, or informative meioses; consequently, co-segregation cannot be assessed and no PP1 strength can be assigned.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The case contains no gene-level analysis demonstrating that F5 has a low rate of benign missense variation, and it does not establish that missense variants are a common disease mechanism for the relevant F5 disorder under the PP2 definition. The observed frequency of this particular variant in gnomAD cannot substitute for both required gene-level PP2 findings.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule is ACMG/AMP PP4: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The supplied case evidence does not provide a patient phenotype, family history, or a disease-specific clinical description for this interpretation, so phenotype specificity cannot be judged.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD v4.1 reports 450 homozygotes, but the available population record does not establish that these individuals were healthy adults, does not document their clinical status, and does not establish that full penetrance is expected at an early age for the relevant F5 disorder. A homozygote count in a population database alone therefore cannot satisfy the healthy-adult observation requirement.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members with documented negative testing for NM_000130.5:c.1601G>A (p.Arg534Gln) are reported. The available evidence therefore does not demonstrate lack of segregation, and the phenocopy and multiple-pathogenic-variant caveats cannot be evaluated.
Lack of segregation in affected members of a family.
The case does not provide a disease-variant spectrum showing that F5 disease is caused primarily by truncating variants. Generic PVS1 context indicates that loss of function is a supported F5 mechanism, but that alone does not establish the BP1 requirement that primarily truncating, rather than missense, variants are known to cause disease.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed from the available evidence. No report documents this variant in trans with a pathogenic variant in a fully penetrant dominant F5 disorder, or in cis with a pathogenic variant in any inheritance pattern. The available records do not establish a second pathogenic allele or phase for this specific variant.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing rule is ACMG/AMP BP5: "Variant found in a case with an alternate molecular basis for disease." No case-level evidence in the supplied materials documents an alternate molecular basis for the disease in a patient carrying this exact variant. Therefore BP5 cannot be evaluated.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000130.5:c.1601G>A in F5 is a missense substitution predicted to produce NP_000121.2:p.(Arg534Gln). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for F5, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000130.5:c.1601G>A in F5 is a missense substitution predicted to produce NP_000121.2:p.(Arg534Gln). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for F5, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000130.5:c.1601G>A in F5 is a missense substitution predicted to produce NP_000121.2:p.(Arg534Gln). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for F5, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000130.5:c.1601G>A in F5 is a missense substitution predicted to produce NP_000121.2:p.(Arg534Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for F5, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in F5, mapped onto the exon structure of NM_000130.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Amish85 / 912 | 0.0933 hom |
| Middle Eastern238 / 6,060 | 0.03913 hom |
| European (non-Finnish)29147 / 1,179,168 | 0.025370 hom |
| European (Finnish)1379 / 64,010 | 0.02211 hom |
| Ashkenazi Jewish567 / 29,592 | 0.0196 hom |
| Remaining individuals1143 / 62,470 | 0.01821 hom |
| South Asian1270 / 91,068 | 0.01424 hom |
| Admixed American460 / 60,026 | 0.00772 hom |
| African/African American282 / 75,012 | 0.0038 |
| East Asian3 / 44,848 | 6.7e-05 |
This variant is present in gnomAD v4.1 (AF= 0.0214324; MAF= 2.14324%, 34574/1613166 alleles, homozygotes = 450) and has highest observed frequency in the Amish population (AF= 0.0932018; MAF= 9.32018%, 85/912 alleles, homozygotes = 3); grpmax FAF= 0.0351821.
Absent from gnomAD v2.1.
This variant is present in gnomAD-Canada v1.0 (AF= 0.021555000542947116, 397/18418 alleles, homozygotes = 7).
The variant is a missense SNV, so PP3 is evaluated through the REVEL path only. The governing generic threshold for PP3 supporting is REVEL >= 0.644, but no REVEL score is available for NM_000130.5:c.1601G>A (p.Arg534Gln); therefore PP3 is not met. The available SpliceAI result is not used because splice prediction is not the governing path for a missense variant.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The variant is a missense SNV, so BP4 is evaluated through the REVEL path only. The governing generic threshold for BP4 supporting is REVEL <= 0.29, but no REVEL score is available for NM_000130.5:c.1601G>A (p.Arg534Gln); therefore BP4 is not met. The available SpliceAI result is not used because splice prediction is not the governing path for a missense variant.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000130.5:c.1601G>A in F5 is a missense substitution predicted to produce NP_000121.2:p.(Arg534Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for F5, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. 1 cited in the classification.
The term "Factor V Leiden" refers to the specific guanine to adenine substitution at nucleotide 1691 in the Factor V gene, which predicts the substitution of glutamine for arginine at the Arg 506 APC cleavage site.
Location Pathogenic Mechanisms and Molecular Basis, page 2; Testing, page 2
Context Review article summarizing molecular mechanism and clinical studies of Factor V Leiden; no assay or cohort specific to p.(R534Q) is described.
Since the first report of activated protein C resistance (APC-R) in 1993,1 and later the demonstration of the Arg506Gln mutation in coagulation factor V (factor V Leiden, FVL) as the genetic defect responsible for most APC-R cases,2-4 numerous studies have established FVL as the most frequent hereditary thrombophilic disorder predisposing carriers to venous thrombosis.
Introduction, paragraph 1; Results, genotype-frequency paragraph; Table 2
The remaining 19 variants in 17 genes have so far failed to support a statistically significant influence on the risk of VTE.
Discussion
Factor V Leiden (FVL; R506Q), the most common known inherited risk factor for thrombosis, results from a base change from G to A at position1691 of the gene encoding coagulation Factor V.
Clinical Considerations, “Definitions used by evaluation of genomic applications in practice and prevention”; Table 2
Factor V Leiden R506Q is a single base mutation in the factor V gene, which eliminates 1 of its 3 activated protein C cleavage sites.
Results, Venous thromboembolism; Interpretation, mechanistic discussion
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.0214324; MAF= 2.14324%, 34574/1613166 alleles, homozygotes = 450) and has highest observed frequency in the Amish population (AF= 0.0932018; MAF= 9.32018%, 85/912 alleles, homozygotes = 3); grpmax FAF= 0.0351821.
Absent from gnomAD v2.1.
This variant is present in gnomAD-Canada v1.0 (AF= 0.021555000542947116, 397/18418 alleles, homozygotes = 7).
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as risk factor (1 clinical laboratory) and as Pathogenic, low penetrance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as drug response by ClinPGx (expert panel). (ClinVarID = 642)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.