ClinVar Genomic variation as it relates to human health

PP4, PM2_moderate, PVS1

The c.296delA pathogenic mutation, located in coding exon 2 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 296, causing a translational frameshift with a predicted alternate stop codon (p.D99Vfs*31). This alteration was previously described in two unrelated families with Birt-Hogg-Dube syndrome, one of which had two family members with fibrofolliculomas and lung cysts, and one of which consisted of an individual with fibrofolliculomas, renal tumors, lung cysts, and multiple pneumothoraces (Toro JR, J. Med. Genet. 2008 Jun; 45(6):321-31; Schmidt LS, Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). Of note, this alteration is also designated as c.751delA in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The FLCN c.296del (p.Asp99Valfs*31, also known as c.751delA) variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in in individuals with Birt-Hogg-Dube (BHD) syndrome (PMID: 15852235 (2005), 18234728 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19802896, 18234728, 21937013, 23757202, 29357828, 15852235)

The FLCN c.296del; p.Asp99ValfsTer31 variant (rs398124534), also published as c.751delA, is reported in the literature in multiple individuals and families affected with Birt-Hogg-Dube syndrome and has been reported to segregate with disease (Mahtani 2021, Schmidt 2005, Toro 2008). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Mahtani K et al. Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases. Hum Hered. 2021;86(1-4):28-33. PMID: 34706366. Schmidt LS et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005 Jun;76(6):1023-33. PMID: 15852235. Toro JR et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31. PMID: 18234728.

This sequence change creates a premature translational stop signal (p.Asp99Valfs*31) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 15852235, 18234728). This variant is also known as c.751delA. ClinVar contains an entry for this variant (Variation ID: 96482). For these reasons, this variant has been classified as Pathogenic.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.