Incidental Cardiovascular Genetic Variants

Definition

Incidental cardiovascular variants are rare variants in CVD-associated genes identified incidentally — that is, not related to the indication for which sequencing was ordered. Sources include exome/genome sequencing performed for unrelated clinical presentations, research biobanks, and direct-to-consumer (DTC) genetic testing. They overlap with, but are broader than, ACMG-defined "secondary findings" (LP/P variants in ACMG-78 genes). The cardinal challenge is that the burden of incidentally identified variants in CVD genes far exceeds the population prevalence of those diseases, making interpretation — rather than detection — the core clinical task.

Key Concepts

ACMG-78 Actionable Gene List — CVD Scope

• 78 genes in the ACMG SF v3.1 list are considered clinically actionable; 42 (54%) are CVD-related, spanning: dyslipidemias (FH: LDLR, APOB, PCSK9), cardiomyopathies (ACM: PKP2/DSP/DSC2/TMEM43/DSG2; DCM: TNNT2/LMNA/FLNC/TTN/BAG3/DES/RBM20/TNNC1; HCM: MYH7/MYBPC3/TNNI3/TPM1/MYL3/ACTC1/PRKAG2/MYL2; RCM: TTR; Fabry: GLA; Pompe: GAA; HH: HFE), inherited arrhythmias (LQTS: KCNQ1/KCNH2/SCN5A; BrS: SCN5A; CPVT: RYR2/CASQ2/TRDN), thoracic aortic disease (FBN1/TGFBR1/TGFBR2/SMAD3/ACTA2/MYH11), and vascular EDS (COL3A1) (sources/incident-gene-aha-2023 — high)
• The ACMG list is dynamic — lags behind expert field consensus; HCM genes are expected to move to CDC Tier 1 (sources/incident-gene-aha-2023 — high)
• CDC 3-tier system: Tier 1 = evidence sufficient to alter management (currently only FH for CVD); Tier 2 = moderate evidence; Tier 3 = insufficient evidence or not ready for routine implementation (polygenic risk scores currently here) (sources/incident-gene-aha-2023 — high)
• Only LP/P variants in ACMG-78 genes should be communicated to patients who have consented to receiving secondary findings (sources/incident-gene-aha-2023 — high)

A Bayesian Framework for Variant Interpretation

The framework integrates the likelihood that a variant is truly disease-associated with the likelihood that the individual carrying it has the implicated disease. (sources/incident-gene-aha-2023 — high)

Step 1 — Pretest Probability of Disease

• Comprehensive medical history + ≥3-generation family history + physical examination + disease-specific clinical testing
• Disease-specific minimum evaluation:
  • Channelopathies: ECG + ≥24h Holter monitor + exercise stress test (if safe)
  • Cardiomyopathy: ECG + echocardiogram; CMR with tissue characterisation can be considered
  • Thoracic aortic disease: echocardiogram; CT or MRI for aortic evaluation can be considered
  • Familial hypercholesterolaemia: serum lipid panel; CT coronary angiography if appropriate
  • Congenital/structural heart disease: ECG + echocardiogram; CMR in selected cases
• Best conducted by a clinician or multidisciplinary team knowledgeable about the implicated disease

Step 2 — Modification by Variant Pathogenicity

• Re-evaluate the LP/P classification assigned by the testing laboratory — do not rely solely on the laboratory's interpretation
• Use ClinVar, ClinGen gene curation, ACMG 2015 criteria; incorporate clinical phenotype into variant reclassification
• Key resources: ClinVar (variant-disease associations), ClinGen (gene validity curation), ACMG/AMP guidelines
• Pathogenicity classification is dynamic: LP/P and likely benign variants reclassify at 1–8%/year, predominantly toward VUS; VUSs reclassify at even higher rates (sources/incident-gene-aha-2023 — high)

Step 3 — Posttest Probability and Management

• High posttest probability (confirmed LP/P + clinical evidence of disease): Longitudinal surveillance per disease-specific guidelines + cascade testing of first-degree relatives
• Moderate posttest probability (LP/P + absent phenotype): Continued longitudinal follow-up at guideline-directed intervals; cascade testing
• Low posttest probability (disputed gene/variant + absent phenotype): Infrequent or no further follow-up
• This framework should be conducted at, or in close consultation with, a specialised multidisciplinary cardiovascular genetics centre

Longitudinal Variant Follow-Up

• Optimal re-evaluation interval: every 1–3 years, individualized to variant and patient (sources/incident-gene-aha-2023 — high)
• Each follow-up visit: reinterpret genetic variant per updated community consensus; repeat clinical testing; re-evaluate personal and family history; integrate genetic and clinical findings
• Pre-testing counselling should establish that follow-up will be needed long-term, even in phenotype-negative individuals

Cascade Testing from Incidental Variants

• LP/P incidental variants confirmed as disease-associated → cascade genetic testing in first-degree relatives is indicated, regardless of whether the proband has phenotypic evidence of disease
• VUS variants must NOT trigger cascade testing — family members should not be tested on the basis of a VUS (sources/incident-gene-aha-2023 — high)
• Genotype-positive family members → apply the same Bayesian framework
• Any variant found LP/P requires longitudinal follow-up of the individual AND predictive testing of first-degree relatives

VUS Management

• VUSs are generally not communicated to patients from clinical ES/GS (by ACMG standards); however, patient-initiated DTC or research-identified VUSs may still reach clinicians
• Decision to evaluate a VUS within the framework is case-by-case, in partnership with cardiovascular genetics experts
• Segregation analysis (tracking co-segregation with phenotype across family members) is the most powerful mechanism to reclassify a VUS to LP/P (sources/genetic-cmp-jcf-2018)

Special Considerations

Diverse Populations

• Non-European ancestry populations have higher VUS rates due to underrepresentation in reference databases; benign variants more likely misclassified as LP/P (sources/incident-gene-aha-2023 — high)
• The same Bayesian framework applies, with heightened attention to variant re-evaluation over time
• Urgent need to include diverse populations in genomics research cohorts

Pediatric Incidental Variants

• Incidental CVD gene variant frequency in children markedly exceeds disease prevalence — careful multidisciplinary interpretation is essential
• Assent (not just consent) should be sought from children capable of understanding implications
• Timely referral to paediatric cardiovascular genetics centres is recommended (sources/incident-gene-aha-2023 — high)

Pharmacogenomic Incidental Findings

• ~1% of patients undergoing pharmacogenomic testing may have incidental findings affecting a medication they are currently taking
• No uniform reporting standards exist for pharmacogenomic incidental findings; pretest counselling is strongly recommended (sources/incident-gene-aha-2023 — high)

Contradictions / Open Questions

• Variant burden vs disease prevalence gap: The frequency of incidentally identified LP/P variants exceeds the prevalence of most CVDs, meaning that many LP/P-designated variants will not cause disease. The false-positive rate of current variant classification systems at population scale is unknown and likely significant. (sources/incident-gene-aha-2023 — high)
• Laboratory inconsistency: Multiple studies document significant inter-laboratory variability in variant pathogenicity classification for the same variant (Amendola et al. 2016; Bland et al. 2018). The Bayesian framework recommends re-evaluating the laboratory's assessment — but this requires specialist expertise not available in most clinical settings. (sources/incident-gene-aha-2023 — high)
• VUS clinical limbo: The recommendation is to not communicate VUSs from clinical testing and not use them for cascade testing. In practice, probands with inherited cardiomyopathies or channelopathies carry VUSs in the majority of cases — meaning most families cannot access genetic-informed cascade testing despite having a likely heritable condition. (sources/incident-gene-aha-2023 — high; sources/genetic-cmp-jcf-2018 — very high)
• Diverse populations and equity: Non-European ancestry individuals face systematically higher VUS rates, making the Bayesian framework harder to apply meaningfully. This inequality is acknowledged but no specific corrective framework is provided. (sources/incident-gene-aha-2023 — high)

Connections

• Related to concepts/Variant-Reclassification — 1–8%/year reclassification rate; VUS management
• Related to concepts/Cascade-Family-Screening — LP/P-only cascade rule; posttest probability framework
• Related to concepts/Cardiogenetic-Centers — multidisciplinary role in incidental variant evaluation
• Related to concepts/DTC-Genetic-Testing — DTC as a source of incidental CVD variants
• Related to concepts/Genetic-Testing-in-Cardiomyopathy — cardiomyopathy gene evaluation context
• Related to concepts/Familial-Hypercholesterolemia — CDC Tier 1 CVD gene (only one currently)
• Related to entities/HCM — ACMG-78 HCM genes
• Related to entities/DCM — ACMG-78 DCM genes
• Related to entities/Long-QT-Syndrome — ACMG-78 LQTS genes
• Related to entities/Brugada-Syndrome — SCN5A incidental findings
• Related to entities/CPVT — RYR2/CASQ2/TRDN; cascade testing rules
• Related to entities/ATTR-Amyloidosis — TTR as ACMG-78 gene
• Related to entities/Anderson-Fabry-Disease — GLA as ACMG-78 gene

Sources

• sources/genetic-cmp-jcf-2018
• sources/incident-gene-aha-2023