genes associated with thromboembolism?
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genes associated with thromboembolism?
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venous thromboembolism genetic risk factors
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I now have comprehensive data from Goldman-Cecil Medicine and multiple textbook sources. Here is a thorough answer:
Genes Associated with Thromboembolism (Thrombophilia)
Venous thromboembolism (VTE) arises from the interaction of an inherited genetic predisposition (primary hypercoagulable state) with an acquired trigger (secondary hypercoagulable state). The following genes are established contributors.
1. Factor V Gene (F5) - Factor V Leiden Mutation
- Mutation: G1691A point mutation (Arg504Gln substitution)
- Mechanism: Renders Factor Va resistant to inactivation by activated Protein C (APC resistance), allowing unregulated thrombin generation
- Prevalence: 3-8% of healthy White/European populations; much lower in African and Asian populations
- VTE risk: Heterozygosity - 5 to 10x increased risk; Homozygosity - 50 to 100x increased risk
- Combined with prothrombin G20210A: Risk of first VTE rises to 20-60x
- Note: The most common inherited thrombophilia, found in 10-65% of patients with VTE
(Goldman-Cecil Medicine, p. 787-789; Medical Physiology)
2. Prothrombin Gene (F2) - G20210A Mutation
- Mutation: G-to-A transition at nucleotide 20210 in the 3' untranslated region of the prothrombin gene
- Mechanism: Leads to elevated plasma prothrombin levels, increasing thrombin generation
- Prevalence: 1-6% in the general (White) population; found in 3-8% of unselected VTE patients
- VTE risk: 1.5 to 3.8x increased risk of first VTE
- The second most common inherited thrombophilia
(Goldman-Cecil Medicine, p. 789)
3. SERPINC1 Gene - Antithrombin (AT-III) Deficiency
- Mechanism: Antithrombin III is the major serine protease inhibitor of thrombin, factor Xa, IXa, XIa, and XIIa. Deficiency allows these coagulant proteases to act unchecked.
- Inheritance: Autosomal dominant; most affected patients are heterozygotes with AT activity ~40-60% of normal
- Types:
- Type I: Quantitative deficiency (reduced synthesis/stability)
- Type II: Qualitative defect (point mutations causing dysfunctional protein)
- Prevalence: 0.02-0.3% in the general population; 1-2% of unselected VTE patients
- VTE risk: 5-8x increased risk of first VTE; one of the highest-risk thrombophilias
- Homozygosity (most forms) is likely lethal in utero from thrombosis
(Goldman-Cecil Medicine, p. 789)
4. PROC Gene - Protein C Deficiency
- Mechanism: Protein C is a vitamin K-dependent anticoagulant that, when activated, inactivates Factors VIIIa and Va. Deficiency impairs regulation of fibrin generation.
- Inheritance: Autosomal dominant
- Prevalence: ~1 in 200-500 general population; 2-5% of VTE patients
- VTE risk: 5-8x increased risk of first VTE
- Homozygous deficiency causes neonatal purpura fulminans (widespread thrombosis)
- Types:
- Type I: Quantitative deficiency (frameshift, nonsense, or missense mutations)
- Type II: Qualitative defect (abnormal activation/function)
(Goldman-Cecil Medicine, p. 789)
5. PROS1 Gene - Protein S Deficiency
- Mechanism: Protein S is the principal cofactor of activated Protein C. Its deficiency mimics Protein C deficiency, impairing inactivation of Factors VIIIa and Va. Only free Protein S (normally ~35-40% of total) is functionally active.
- Inheritance: Autosomal dominant
- Prevalence: ~1 in 500 general population; 1-3% of VTE patients
- VTE risk: 1.7-8x increased risk (levels far below normal are needed for significant risk)
- Types: Type I (quantitative), Type II (qualitative), Type III (low free protein S with normal total)
- Homozygous deficiency can also cause neonatal purpura fulminans
(Goldman-Cecil Medicine, p. 789)
6. MTHFR Gene - Hyperhomocysteinemia
- Mutations: C677T and A1298C polymorphisms
- Mechanism: MTHFR converts homocysteine to methionine. Mutations reduce enzyme activity, raising plasma homocysteine, which is prothrombotic (endothelial damage and altered coagulation factor activity). Cystathionine beta-synthase (CBS) mutations cause severe hyperhomocysteinemia.
- Risk: Moderate; risk correlates with degree of homocysteine elevation. The common C677T polymorphism alone is NOT a strong independent risk factor for thrombosis according to current evidence.
- Note: Treatable with folate, B6, and B12 supplementation
(Goldman-Cecil Medicine; Mulholland Surgery; Berek & Novak's Gynecology)
Summary Table (from Goldman-Cecil Medicine)
| Thrombophilia | General Population | VTE Patients | First VTE Risk | Recurrent VTE Risk |
|---|---|---|---|---|
| Antithrombin deficiency | 0.02-0.3% | 1-2% | 5-8x | 2.5x |
| Protein C deficiency | 0.2-0.5% | 2-5% | 5-8x | 2.5x |
| Protein S deficiency | 0.5% | 1-3% | 1.7-8x | 2.5x |
| Factor V Leiden | 3-8% | 10-65% | 5-10x | 1.3x |
| Factor II G20210A | 1-6% | 3-8% | 1.5-3.8x | 1.4x |
| Factor V Leiden + Factor II G20210A | 0.01% | - | 20-60x | 2.5x |
Additional/Emerging Genetic Risk Factors
Recent 2024 GWAS and functional genomics studies (Underwood et al., JTH 2024) have identified additional loci beyond classical thrombophilia genes, including:
- F8 (Factor VIII) - elevated levels are an independent VTE risk factor
- ABO blood group gene - Non-O blood groups (A, B, AB) are associated with higher Factor VIII and vWF levels and increased VTE risk
- FGA/FGB/FGG (Fibrinogen genes) - variants affecting fibrin clot structure
- STAB2 (Stabilin-2) - identified in GWAS as a VTE-associated locus influencing FVIII clearance
- KNG1 (kininogen) - influences contact pathway and factor XI levels
Key Clinical Points
- Inherited thrombophilias primarily increase venous (not arterial) thromboembolism risk
- Most thrombotic events are "provoked" - a genetic predisposition is unmasked by an acquired trigger (surgery, pregnancy, immobilization, estrogen use, cancer)
- Testing is recommended for unprovoked VTE, strong family history, or VTE at unusual sites
- Standard thrombophilia panel includes: Antithrombin, Protein C, Protein S, Factor V Leiden mutation, Prothrombin G20210A mutation, +/- Lupus anticoagulant/anticardiolipin antibodies
kindly brief the ACMG/AMP guidelines for variant classification.
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ACMG AMP variant classification guidelines
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ACMG AMP 2015 variant classification guidelines criteria summary pathogenic benign
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https://pmc.ncbi.nlm.nih.gov/articles/PMC4544753
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I now have comprehensive information to provide a thorough briefing. Here is a complete overview:
ACMG/AMP Guidelines for Variant Classification (Richards et al., 2015)
Published as a joint consensus recommendation by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (PMC4544753), these guidelines standardized the language and process for interpreting sequence variants in genes associated with Mendelian disorders.
The Five-Tier Classification System
| Class | Meaning | Probability threshold |
|---|---|---|
| Pathogenic (P) | Variant is disease-causing | >99% certainty |
| Likely Pathogenic (LP) | Variant is probably disease-causing | >90% certainty |
| Variant of Uncertain Significance (VUS) | Evidence is insufficient or contradictory | Cannot classify |
| Likely Benign (LB) | Variant is probably not disease-causing | >90% certainty benign |
| Benign (B) | Variant is not disease-causing | >99% certainty |
The terms "mutation" and "polymorphism" are explicitly retired - all DNA changes are called "variants," avoiding the negative connotation of "mutation" and the false reassurance of "polymorphism." - Emery's Elements of Medical Genetics and Genomics, p. 73
The 28 Evidence Criteria
There are 16 pathogenic and 12 benign criteria, each assigned a strength level.
Pathogenic Criteria (P-side)
Very Strong (PVS)
| Code | Description |
|---|---|
| PVS1 | Null variant (nonsense, frameshift, canonical splice site ±1/2, initiation codon, single/multi-exon deletion) in a gene where loss of function is the known disease mechanism. Requires careful application - a decision tree governs its use (updated post-2015). |
Strong (PS)
| Code | Description |
|---|---|
| PS1 | Same amino acid change as a previously established pathogenic variant, even if the nucleotide change differs (e.g., different codon achieving the same missense) |
| PS2 | De novo variant (both paternity and maternity confirmed) in a patient with the disease and no family history |
| PS3 | Well-established functional assays show deleterious effect on gene/protein function. Assay must be validated - strength is now evidence-calibrated (updated 2019) |
| PS4 | Variant prevalence in affected individuals is significantly higher than in controls (OR >5.0 with confidence intervals not overlapping 1.0, or present in ≥5 unrelated patients) |
Moderate (PM)
| Code | Description |
|---|---|
| PM1 | Variant located in a mutational hotspot or well-established functional domain (e.g., active site) with no benign variation |
| PM2 | Absent from controls (or at extremely low frequency) in population databases such as gnomAD |
| PM3 | For recessive disorders: detected in trans with a pathogenic variant |
| PM4 | Protein length change due to in-frame deletion/insertion in a non-repeat region, or stop-loss variant |
| PM5 | Novel missense at an amino acid position where a different missense change is known to be pathogenic |
| PM6 | Assumed de novo (paternity/maternity not confirmed) |
Supporting (PP)
| Code | Description |
|---|---|
| PP1 | Co-segregation with disease in multiple affected family members |
| PP2 | Missense variant in a gene with low tolerance for missense variation, where missense is a common disease mechanism |
| PP3 | Multiple computational/in silico tools predict deleterious effect on gene/protein (now tied to a validated score threshold with a measured odds ratio - updated 2022) |
| PP4 | Patient's phenotype or family history is highly specific for a disease with a single genetic etiology |
| PP5 | Reputable source recently reports variant as pathogenic (limited internal evidence available) |
Benign Criteria (B-side)
Stand-Alone (BA) - Single criterion is sufficient for Benign classification
| Code | Description |
|---|---|
| BA1 | Allele frequency >5% in population databases (gnomAD, ExAC, etc.) - stands alone as sufficient for Benign |
Strong (BS)
| Code | Description |
|---|---|
| BS1 | Allele frequency greater than expected for the disorder |
| BS2 | Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance |
| BS3 | Well-established functional assays show no damaging effect on protein function or splicing |
| BS4 | Lack of segregation in affected members of a family |
Supporting (BP)
| Code | Description |
|---|---|
| BP1 | Missense variant in a gene where only truncating variants cause disease |
| BP2 | Observed in trans with a pathogenic variant for a fully penetrant dominant disorder; or in cis with a pathogenic variant |
| BP3 | In-frame deletion/insertion in a repetitive region without a known function |
| BP4 | Multiple computational tools predict benign effect (concordant, calibrated) |
| BP5 | Variant found in a case with an alternate molecular basis for disease |
| BP6 | Reputable source recently reports variant as benign |
| BP7 | A synonymous (silent) variant where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved |
Combining Rules (Table 5 Logic)
These rules combine applied criteria into a final classification. Think of them as a lookup table, not a calculation:
Pathogenic
- 1x PVS1 + 1x PS, OR
- 1x PVS1 + 2x PM, OR
- 1x PVS1 + 1x PM + 1x PP, OR
- 1x PVS1 + 2x PP, OR
- 2x PS, OR
- 1x PS + 3x PM, OR
- 1x PS + 2x PM + 2x PP, OR
- 1x PS + 1x PM + 4x PP
Likely Pathogenic
- 1x PVS1 + 1x PM, OR
- 1x PS + 1-2x PM, OR
- 1x PS + 3x PP, OR
- 3x PM, OR
- 2x PM + 2x PP, OR
- 1x PM + 4x PP
Benign
- 1x BA1, OR
- 2x BS
Likely Benign
- 1x BS + 1x BP, OR
- 2x BP
VUS (default)
- Any criteria not meeting the above thresholds, or when pathogenic and benign criteria are contradictory
Types of Evidence Used
All 28 criteria draw on these evidence categories:
- Population data - allele frequencies in gnomAD, ExAC, 1000 Genomes
- Computational/in silico data - SIFT, PolyPhen, CADD, SpliceAI, etc.
- Functional data - cell-based assays, animal models, biochemical studies
- Segregation data - co-segregation with disease across family members
- De novo data - confirmed de novo occurrence in the proband
- Allelic data - cis vs. trans configurations with other variants
- Database/literature data - ClinVar, HGMD, published case reports
Major Updates Since 2015
The framework has been progressively refined:
| Year | Update | Impact |
|---|---|---|
| 2018 | PVS1 decision tree (Abou Tayoun et al.) | PVS1 now uses a structured flowchart; strength can be downgraded to strong/moderate based on variant type and gene context |
| 2019 | PS3/BS3 calibration (Brnich et al.) | Functional assay strength must be evidence-based, not assumed; assay validation is required |
| 2020 | PM2 refinement | Extremely low (not just absent) frequency counts; gnomAD sub-population awareness |
| 2022 | PP3/BP4 calibration (Pejaver et al.) | In silico scores now tied to Bayesian-calibrated odds ratios; REVEL score ≥0.932 = moderate pathogenic evidence |
| 2024 (ongoing) | ClinGen gene/disease-specific guidelines | Disease/gene-specific variant curation expert panels (VCEPs) are rewriting criterion weights for individual genes |
Clinical Application Notes
- Guidelines apply to germline variants in Mendelian disease genes - separate frameworks exist for somatic cancer variants (AMP/ASCO/CAP 2017) and CNVs
- VUS is not a diagnosis - it should not be used for clinical decision-making; reclassification over time is expected as evidence accumulates
- Classification is gene-disease context dependent - the same variant may be classified differently in different disease contexts
- ClinVar is the primary public repository for submitted variant classifications using this framework
- "Likely" categories imply ≥90% certainty - Tietz Textbook of Laboratory Medicine, 7th Ed.
The original paper - Richards et al., Genetics in Medicine 2015 - remains the foundational reference, with ClinGen's variant curation expert panels continuously refining gene-specific thresholds as of 2024-2026.
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