Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000239662 | SCV001575074 | pathogenic | Birt-Hogg-Dube syndrome | 2022-06-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FLCN protein in which other variant(s) (p.Trp533Arg) have been determined to be pathogenic (Invitae; external communications). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant disrupts the FNIP1/2 interaction domain, which 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. ClinVar contains an entry for this variant (Variation ID: 253260). This premature translational stop signal has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome (PMID: 28558743). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp553*) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the FLCN protein. |
| Ambry Genetics | RCV002401949 | SCV002706504 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-01 | criteria provided, single submitter | clinical testing | The p.W553* pathogenic mutation (also known as c.1658G>A), located in coding exon 11 of the FLCN gene, results from a G to A substitution at nucleotide position 1658. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of FLCN, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 27 amino acids of the protein. This alteration has been observed in multiple individuals who have a personal and/or family history that is consistent with FLCN-associated disease (Ambry internal data; Liu Y et al. Orphanet J Rare Dis. 2017 05;12:104). Based on internal structural assessment, this alteration disrupts the C-terminal DENN-like domain, which is a guanine nucleotide exchange factor implicated in FLCN’s role in membrane trafficking (Ambry internal data; Nookala RK et al. Open Biol. 2012 Aug;2:120071; Dodding MP. Small GTPases. 2017 04;8:100-105; Schmidt LS et al. Gene. 2018 Jan;640:28-42). Based on the majority of available evidence to-date, this alteration is interpreted as a disease-causing mutation. |
| Genomic Diagnostic Laboratory, |
RCV000239662 | SCV000298094 | uncertain significance | Birt-Hogg-Dube syndrome | 2016-07-18 | flagged submission | clinical testing |