The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F, further genotype/phenotype correlation data

Genet Med. 2011 Dec;13(12):1042-4. doi: 10.1097/GIM.0b013e318228efb2.


Purpose: : Recently, a major CLIA-certified commercial laboratory began offering an extended cystic fibrosis (CF) carrier screening panel containing 103 variants including p.L997F. Our laboratory has already received two invasive prenatal diagnostic samples where one parent carries a classic CF mutation and the other carries p.L997F. One fetus inherited both variants.

Methods: : We queried our databases containing >2500 CF sequencing analyses to find all individuals with the p.L997F variant. For all compound heterozygous patients, clinical information was obtained by a genetic counselor telephoning the medical provider.

Results: : There were four compound heterozygous patients carrying the p.L997F variant and a second pathogenic CF allele. Three patients were discovered by newborn screening and were asymptomatic at ages 28, 40, and 60 months, respectively. The fourth individual is currently aged 10 years and has the diagnosis of atypical CF with recurrent pancreatitis, sinusitis with nasal polyps, and mild lung disease. His length and weight are in the 90th and 75th centile, respectively. The fifth patient was a compound heterozygote for p.F508del and a complex allele containing p.L997F and a deletion of exons 2-9. This patient has the diagnosis of classical CF.

Conclusion: : The p.L997F variant is not a classical CF mutation, and its inclusion in population-based carrier screening panels is a disservice to couples who may make poorly informed reproductive decisions based on incorrect assumptions.

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • Cystic Fibrosis / diagnosis
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • DNA Mutational Analysis
  • Exons
  • Genetic Association Studies
  • Genetic Counseling
  • Genetic Testing / ethics*
  • Genetic Testing / methods
  • Genetic Testing / standards
  • Genotype
  • Heterozygote
  • Humans
  • Infant, Newborn
  • Mutation*
  • Neonatal Screening / methods*
  • Phenotype
  • Population Surveillance*


  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator