Abstract Introduction The FLCN gene is implicated in Birt-Hogg-Dubé syndrome (BHDS), a condition characterized by pulmonary cysts, renal tumors, and skin lesions. The c.1126TC (p.Trp376Arg) variant in FLCN (ClinGen Canonical Allele ID:CA398532274) is currently classified as a Variant of Uncertain Significance (VUS) by ClinVar, Invitae and Ambry. We describe a family with this variant and a clinical syndrome consistent with BHDS, suggesting pathogenicity. Description A 27-year-old gentleman presented with months of dyspnea, chest wall tightness and palpitation all at rest, and one episode of dizziness and syncope during flight; he was found to have a spontaneous left pneumothorax. He had non-labored breathing with normal vital signs, oxygenation and laboratory results. After chest tube drainage, chest CT revealed multiple thin-walled cysts within lung parenchyma, distributed mainly in the lower lobes. He underwent VATS wedge resection of 7 moderate/large blebs within the left upper and lower lobes, parietal pleurectomy and chemical pleurodesis. Subsequent genetic testing result was heterozygous for FLCN gene variant c.1126TC (p.Trp376Arg). Further investigation of his family history revealed that his mother also had spontaneous pneumothorax and eventually died from glioblastoma. Tumor sequencing revealed 53% of reads with the same variant, suggesting germline origin. Imaging showed multiple lower lobe and paramediastinal thin-walled cysts. His brother with the same FLCN VUS, renal cysts and thyroid nodules, has no lung disease or fibrofolliculomas identified to date. Result Presence of this FLCN variant in three family members, two of whom have classic BHDS. Discussion Although currently classified as a VUS by ClinVar we present multiple lines of evidence indicating that this variant should be upgraded to “Likely Pathogenic” by American College of Medical Genetic and Genomics (ACMG) guidelines. These data include BHD-specific phenotype in at least two affected relatives, co-segregation of the variant with disease across two generations, and the variant not appearing in large genetic databases (gnomADv4.1.0). This case series highlights several key points: 1. Variant Classification Challenges: The discrepancy between literature-reported pathogenicity and current database classification underscores the need for updated evidence. 2. Familial Evidence Supporting Pathogenicity: Co-segregation of the variant across three affected individuals strengthens the case for reclassification. 3. Importance of Case-Based Reporting: Case series like this contribute valuable data to variant databases and clinical interpretation. 4. Implications for Genetic Counseling and Surveillance: Reclassification could impact screening recommendations and management strategies for family members. Conclusion Results from the presented family support upgrade of the FLCN c.1126TC (p.Trp376Arg) variant from VUS to “Likely Pathogenic” status. This abstract is funded by: None
Saber et al. (Fri,) studied this question.