Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000822550 | SCV000963359 | pathogenic | Birt-Hogg-Dube syndrome | 2019-03-18 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon 14 of the FLCN gene. The 5' boundary is likely confined to intron 13. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Deletion of exon 14 has been observed in individuals with features of Birt-Hogg-Dub_x0001_e syndrome (PMID: 20413710, 24393238, 27229674). This variant disrupts the C-terminus of the FLCN protein, which contains the minimal binding domain for interaction with FNIP1/2 proteins (residues 517-579) (PMID: 17028174, 18403135). This domain has been shown to be important for AMPK-mediated mTOR signaling pathways (PMID: 17028174, 18403135, 18663353, 22977732). While functional studies have not been performed to directly test the effect of this variant on FLCN protein function, this suggests that disruption of this region of the protein may be causative of disease. Other variant(s) that disrupt this region (p.Arg527*, p.Gln533*) have been determined to be pathogenic (PMID: 15852235, 19802896, Invitae). For these reasons, this variant has been classified as Pathogenic. |