ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1177-5_1177-3del (rs767671406)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000239690 SCV000271788 likely pathogenic Multiple fibrofolliculomas 2021-01-06 criteria provided, single submitter clinical testing The c.1177-5_1177-3delCTC variant in FLCN has been reported in at least 2 individuals with Birt-Hogg-Dube syndrome (BHDS) and 6 individuals with suspected BHDS and segregated with clinical features of the disease in 3 affected individuals from 2 families (Kunogi 2010 PMID: 20413710, Kunogi Okura 2013 PMID: 24190151, Johannesma 2014 PMID: 24994497, Furuya 2016 PMID: 27220747, Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369, Liu 2017 PMID: 28558743). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 228691) and has identified in 0.005% (1/21382) of Finnish and 0.002% (2/111570) of European chromosomes by gnomAD ( This variant is a deletion of 3 nucleotides in the 3' splice region. In vitro minigene splicing assays functional studies support an impact on splicing, through exon 11 skipping, that leads to a truncated or absent protein (Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Birt-Hogg-Dube syndrome. ACMG/AMP Criteria applied: PS4_Strong, PM2_Supporting, PP1, PS3_Moderate.
Ambry Genetics RCV000217238 SCV000273659 pathogenic Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing The c.1177-5_1177-3delCTC intronic pathogenic mutation is located 3 nucleotides before coding exon 8 of the FLCN gene. This variant results from a deletion of 3 nucleotides (CTC) from positions c.1177-5 to c.1177-3. This variant has been reported in multiple unrelated individuals with features of Birt-Hogg-Dube (BHD) syndrome, or symptoms consistent with BHDS (Lim DH et al. Hum Mutat. 2010 Jan;31(1):E1043-51; Okura M et al. Intern. Med. 2013;52(21):2453-5; Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Bartram MP et al. BMC Med. Genet. 2017 May;18:53) and has been found to segregate with disease (Okura M et al. Intern Med. 2013;52(21):2453-5; Ambry Internal Data). In addition, rtPCR and mini-gene splicing assays both indicate that this alteration results in exon skipping and a transcript lacking coding exon 8 (Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Rossing M et al. J. Hum. Genet. 2017 Feb;62(2):151-157; Bartram MP et al. BMC Med. Genet. 2017 May;18(1):53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239690 SCV000298072 uncertain significance Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000255836 SCV000321661 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing This variant is denoted FLCN c.1177-5_1177-3delCTC or IVS10-5_IVS10-3delCTC and consists of a deletion of three nucleotides at the -5 to -3 position in intron 10 of the FLCN gene. The normal sequence with the bases that are deleted in brackets is cctc[delctc]agAC, where the capital letters are exonic and lowercase are intronic. RT-PCR and mini-gene assays have shown that FLCN c.1177-5_1177-3delCTC leads to abnormal splicing, resulting in the skipping of exon 11 and ultimately protein truncation (Kunogi 2013, Bartram 2017, Rossing 2017). This variant has been observed in multiple individuals with clinical features suggestive of Birt-Hogg-Dube syndrome (Kunogi 2010, Kunogi 2013, Johannesma 2014, Furuya 2016, Bartram 2017, Rossing 2017). FLCN c.1177-5_1177-3delCTC was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on the currently available evidence, we consider FLCN c.1177-5_1177-3delCTC to be pathogenic.
Invitae RCV000239690 SCV000632828 pathogenic Multiple fibrofolliculomas 2020-08-05 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the FLCN gene. It does not directly change the encoded amino acid sequence of the FLCN protein, but it falls immediately upstream of the consensus splice acceptor site 5' of exon 11. This variant is present in population databases (rs767671406, ExAC 0.003%). This variant has been reported in many individuals and families affected with Birt–Hogg–Dubé syndrome, and segregated with disease in one of these families (PMID: 24190151, 20413710, 19802896, 24994497, 27734835, 27220747). ClinVar contains an entry for this variant (Variation ID: 228691). Experimental studies have shown that this variant causes skipping of exon 11, likely resulting in an absent or disrupted protein product (PMID: 27734835, 28499369). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000217604 SCV001157399 pathogenic not specified 2018-08-19 criteria provided, single submitter clinical testing The FLCN c.1177-5_1177-3delCTC variant (rs767671406) is reported in the literature in individuals with Birt-Hogg-Dube syndrome (Bartram 2017, Furuya 2016, Johannesma 2014, Kunogi Okura 2013, Kunogi 2010), and it has been shown to co-segregate with disease (Kunogi Okura 2013). Functional analyses demonstrate that this intronic variant causes exon skipping ultimately leading to a truncated and destabilized protein (Bartram 2017). This variant is reported by multiple laboratories in ClinVar (Variation ID: 228691). It is found in the general population with a low overall allele frequency of 0.001% (3/243776 alleles) in the Genome Aggregation Database. Computational algorithms also predict that the variant has an impact on the nearby canonical splice acceptor (Alamut v.2.10), consistent with functional studies. Based on available information, this variant is considered pathogenic. REFERENCES Bartram MP et al. Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC Med Genet. 2017 May 12;18(1):53. Furuya M et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. Clin Genet. 2016 Nov;90(5):403-412. Johannesma PC et al. Spontaneous pneumothorax as indicator for Birt-Hogg-Dube syndrome in paediatric patients. BMC Pediatr. 2014 Jul 3;14:171. Kunogi Okura M et al. Pneumothorax developing for the first time in a 73-year-old woman diagnosed with Birt-Hogg-Dube syndrome. Intern Med. 2013;52(21):2453-5. Kunogi M et al. Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010 Apr;47(4):281-7.

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