Clinical Implications and Management for Individuals with CFTR Pathogenic Variant c.1624G>T (p.G542*)
Individuals with the pathogenic variant c.1624G>T (p.G542) in the CFTR gene have cystic fibrosis and require comprehensive multidisciplinary care focused on pulmonary health, pancreatic function monitoring, and genetic counseling.*
Variant Classification and Significance
The c.1624G>T (p.G542*) variant is a well-established pathogenic variant in the CFTR gene that:
- Is included in the American College of Medical Genetics and Genomics (ACMG) recommended minimum variant set for CF carrier screening 1
- Creates a premature stop codon (nonsense mutation) resulting in a truncated, non-functional CFTR protein
- Is classified as a Class I mutation, which typically results in no functional CFTR protein production 2
- Has a higher frequency in Mexican and Spanish populations (7.2% and 8% of CF chromosomes, respectively) compared to the worldwide average (3.4%) 3
Clinical Manifestations and Phenotype
Patients with the G542* variant typically present with:
- Mild to moderate pulmonary disease 3
- Potential for hepatobiliary involvement (higher frequency observed in patients with liver manifestations) 3
- Classic CF manifestations including bronchiectasis, chronic respiratory infections, pancreatic insufficiency, and elevated sweat chloride levels
Management Recommendations
Pulmonary Care
- Regular pulmonary function testing
- Airway clearance techniques
- Aggressive treatment of respiratory infections
- CFTR modulator therapy evaluation (note: nonsense mutations like G542* typically do not respond to current CFTR modulators)
Gastrointestinal Management
- Pancreatic enzyme replacement therapy if pancreatic insufficient
- Nutritional support and monitoring
- Regular liver function assessment due to increased risk of hepatobiliary involvement with this variant
Genetic Counseling
- Genetic counseling should be provided at the time of diagnosis, during adolescence, and at family planning stages 1
- Discussion of autosomal recessive inheritance pattern
- Carrier testing for family members
- Reproductive options including preimplantation genetic diagnosis
Family Implications
- Carrier testing for siblings and other at-risk relatives
- Assistance with disseminating information to relatives 1
- Discussion of reproductive risks and options for family members
Surveillance Recommendations
- Regular pulmonary function testing (every 3-6 months)
- Annual influenza vaccination
- Annual liver function tests
- Regular nutritional assessments
- Monitoring for CF-related diabetes
- Bone density screening in adults
Important Considerations
Variant Interpretation: While c.1624G>T (p.G542*) is a well-established pathogenic variant, it's important to recognize that variant classifications can change over time as new evidence emerges 4. Periodic reassessment of variant significance may be warranted.
Comprehensive Testing: When genetic testing is performed, it's important to ensure that appropriate testing methodology is used, as tumor genomic sequencing alone may miss clinically significant germline variants 5.
Psychosocial Support: Evaluation of psychological and emotional support needs for patients and their caregivers is essential, with processes for referring to support services in place 1.
Follow-up Genetic Counseling: Patients should revisit genetic counseling in mid to late teenage years and again at times of family planning to ensure understanding of their diagnosis, management recommendations, and reproductive risks 1.
By following these recommendations, patients with the CFTR c.1624G>T (p.G542*) pathogenic variant can receive appropriate care to manage their condition and make informed decisions about their health and family planning.