ClinVar Miner

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

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Total submissions: 7
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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 2020-09-22 criteria provided, single submitter clinical testing The p.Y463* pathogenic mutation (also known as c.1389C>G), located in coding exon 9 of the FLCN gene, results from a C to G substitution at nucleotide position 1389. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals with Birt-Hogg-Dubé syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76(6):1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45(6):321-31), including one large family where the mutation co-segregated with disease in six of six affected individuals (Nickerson ML et al. Cancer Cell. 2002 Aug;2(2):157-64). 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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 2020-12-11 criteria provided, single submitter clinical testing Nonsense 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 2016); Also known as c.1844C>G; This variant is associated with the following publications: (PMID: 19802896, 15852235, 18234728, 23784378, 25525159, 12204536, 25126726, 28869776, 19562744, 29357828, 31008171)
Invitae RCV000003534 SCV000549459 pathogenic Multiple fibrofolliculomas 2020-11-01 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-Dubé 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000003534 SCV001761634 pathogenic Multiple fibrofolliculomas 2021-07-15 criteria provided, single submitter clinical testing The FLCN c.1389C>G (p.Tyr463Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant has been reported in several families with Birt-Hogg-Dubé syndrome (PS4; PMID: 12204536, 15852235, 18234728), including one large family where the mutation co-segregated with disease in six of six affected individuals (PP1; PMID: 12204536). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting, PP1.
OMIM RCV000003534 SCV000023692 pathogenic Multiple fibrofolliculomas 2009-09-01 no assertion criteria provided literature only

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