Are the mutations c.68864G>C and c.96235G>A associated with arrhythmogenic cardiomyopathy?

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Last updated: October 22, 2026 • View editorial policy

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Cannot Determine Association Without Gene Identification

The specific mutations c.68864G>C and c.96235G>A cannot be evaluated for their relationship to arrhythmogenic cardiomyopathy without knowing which genes harbor these variants. The nomenclature provided describes only the nucleotide position and change, but does not specify the gene name, making it impossible to assess pathogenicity or disease association.

Why Gene Identity is Critical

The provided evidence comprehensively outlines the genetic architecture of ACM, identifying specific genes with established disease associations 1. However, these mutation designations (c.68864G>C and c.96235G>A) represent:

  • Nucleotide positions within an unspecified gene
  • Base pair changes (G to C, and G to A respectively)
  • No gene context for interpretation

Established ACM Genes for Context

To properly evaluate these variants, you would need to know if they occur in:

High-Evidence Desmosomal Genes

  • PKP2 (plakophilin-2): Most common, 20-46% of ACM cases 1
  • DSP (desmoplakin): 3-20% of cases, associated with left-predominant ACM 1
  • DSG2 (desmoglein-2): 3-20% of cases 1, 2
  • DSC2 (desmocollin-2): 1-15% of cases 1
  • JUP (plakoglobin): 0-1% except in specific populations 1

Non-Desmosomal Genes with Established Association

  • FLNC (filamin C): 0-3%, highly arrhythmogenic left-predominant ACM 1
  • PLN (phospholamban): 0-4%, Dutch founder mutation R14del 1
  • TMEM43: 0-2%, Newfoundland founder mutation 1
  • LMNA (lamin A/C): 0-4% 1
  • TTN (titin): 0-10% 1

Emerging or Uncertain Genes

  • TJP1, ANK2, TP63: Recently proposed with limited evidence 1

Critical Pitfalls in Variant Interpretation

Common errors when evaluating ACM variants:

  • Overinterpretation of missense variants: Initial high prevalence estimates (up to 21%) were artifacts of incorrect adjudication 1
  • Population frequency matters: 0.23% of general population harbors loss-of-function desmosomal variants with only 6% penetrance 1
  • Truncating vs. non-truncating: Loss-of-function (truncating) variants have strongest pathogenicity evidence with significant over-representation in ACM cases 1

What You Need to Proceed

To determine if these mutations are ACM-related, obtain:

  1. Gene name where the variants are located
  2. Protein consequence (missense, nonsense, frameshift, splice site)
  3. Population frequency from databases (gnomAD)
  4. Segregation data if familial cases exist
  5. Clinical phenotype of the affected individual(s)

Variant Classification Framework

Once the gene is identified, classification should follow ClinGen ARVC Gene Curation Expert Panel criteria 1, considering:

  • Gene-disease validity: Is the gene definitively associated with ACM?
  • Variant type: Truncating variants in desmosomal genes have highest pathogenicity
  • Functional evidence: Does the variant disrupt protein function?
  • Segregation: Does it track with disease in families?
  • Population data: Is it absent or extremely rare in controls?

Without gene identification, these variants remain uninterpretable and should be classified as variants of uncertain significance (VUS) at minimum.

References

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.