ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1597C>T (p.Gln533Ter) (rs398124532)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082632 SCV000114674 pathogenic not provided 2013-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000082632 SCV000582956 likely pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The Q533X nonsense variant in the FLCN gene has been reported previously in at least one individual with clinical features of Birt-Hogg-Dube syndrome (Lim et al., 2010). This variant is predicted to cause loss of normal protein function through protein truncation. The Q533X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Based on currently available evidence, Q533X is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Invitae RCV000820903 SCV000961639 likely pathogenic Multiple fibrofolliculomas 2019-12-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FLCN gene (p.Gln533*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of Birt-Hogg-Dub syndrome (PMID: 19802896). ClinVar contains an entry for this variant (Variation ID: 96480). This variant disrupts the C-terminus of the FLCN protein that contains a large portion of the minimal binding domain for interaction with FNIP1/2 proteins (residues 517-579) (PMID: 17028174, 18403135), 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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