ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1389C>G (p.Tyr463Ter) (rs137852929)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166580 SCV000217382 pathogenic Hereditary cancer-predisposing syndrome 2017-04-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000003534 SCV000298081 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000255586 SCV000321666 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing This variant is denoted FLCN c.1389C>G at the cDNA level and p.Tyr463Ter (Y463X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as FLCN c.1844C>G using an alternate transcript, has previously been reported in association with Birt-Hogg-Dubé syndrome (BHD) (Nickerson 2002, Schmidt 2005, Toro 2008). We consider this variant to be pathogenic.
Invitae RCV000003534 SCV000549459 pathogenic Multiple fibrofolliculomas 2019-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 463 (p.Tyr463*) of the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families with Birt-Hogg-Dub syndrome (PMID: 12204536, 15852235, 18234728). ClinVar contains an entry for this variant (Variation ID: 3367). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781382 SCV000919361 pathogenic Pneumothorax, primary spontaneous 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The FLCN c.1389C>G (p.Tyr463X) variant results in a premature termination codon, predicted to cause a truncated or absent FLCN protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. One functional study showed increased interaction with the autophagy kinase ULK1 with this variant as well as impaired binding to the GABA(A) receptor-associated protein and higher levels of sequestome 1 (SQSTM1)( Dunlop_FLCN_Autophagy_2014). This variant is absent in 246200 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. This variant was found in multiple patients with Birt-Hogg-Dube syndrome (Schmidt_FLCN_2005). Taken together, this variant is classified as pathogenic.
OMIM RCV000003534 SCV000023692 pathogenic Multiple fibrofolliculomas 2009-09-01 no assertion criteria provided literature only

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