ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1285dup (p.His429fs) (rs80338682)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130568 SCV000185439 pathogenic Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing The c.1285dupC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a duplication of C at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Pfs*27). This recurrent mutation has been reported in multiple families affected with Birt-Hogg-Dubé syndrome and was shown to result in significant impairment of FLCN protein stability and function (Nickerson ML et al. Cancer Cell. 2002 Aug;2:157-64; Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Nahorski MS et al. Hum. Mutat. 2011 Aug;32:921-9; Nishida C et al. Respir. Med. 2015 Jul;109:923-5; Furuya M et al. Clin. Genet. 2016 Nov;90:403-412; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157; Lee JH et al. Korean J. Intern. Med. 2018 Oct). 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.
Invitae RCV000003529 SCV000261689 pathogenic Multiple fibrofolliculomas 2020-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His429Profs*27) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in individuals with Birt-Hogg-Dubé (BHD) syndrome (PMID: 12471204, 20522427, 17496196, 12204536). This variant is also known as 1733insC, 1740dupC, and 1277insC in the literature. ClinVar contains an entry for this variant (Variation ID: 3363). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000003529 SCV000298076 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000082626 SCV000329354 pathogenic not provided 2021-04-02 criteria provided, single submitter clinical testing Frameshift 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; Published functional studies demonstrate a damaging effect: inactivates gene expression, disrupts protein stability, inhibits tumor suppression, and down-regulates multiple genes involved in TGF-beta signaling (Hong 2010a, Hong 2010b, Nahorski 2011); Also known as 1733insC; This variant is associated with the following publications: (PMID: 21209915, 23784378, 23416984, 12204536, 27229674, 28152038, 12471204, 21538689, 22146830, 23995526, 24346394, 20573232, 25594584, 19850877, 20618353, 18505456, 27220747, 27734835, 28558743, 28690286, 28151982, 29357828, 30360018, 29548312, 28724667, 26387484, 26028485, 28869776, 22148048, 20522427)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508113 SCV000603726 pathogenic not specified 2018-10-03 criteria provided, single submitter clinical testing The FLCN c.1285dupC; p.His429fs variant (rs80338682), also known as 9C, 1733insC, 1740dupC, and 1277insC, is a well-known pathogenic variant that occurs in the mutational sequence hot-spot of eight cytosine nucleotides in exon 11 on the FLCN gene. Both c.1285delC and c.1285dupC have been reported in a number of patients diagnosed with Birt-Hogg-Dube syndrome (see selected references of Khoo 2002, Lopez 2012, Nahorski 2011, Nickerson 2002). It is also classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 3363). Pathogenic FLCN variants are associated with Birt-Hogg-Dube syndrome, an autosomal dominant hereditary cancer syndrome (MIM: 135150). The syndrome can present with a high degree of clinical variability. Offspring of this individual have a 50 percent chance of inheriting the variant. REFERENCES Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet 2002; 39:906-912. Lopez V et al. Birt-Hogg-Dube Syndrome: An Update. Actas Dermosifiliogr. 2012; 103(3):198-206. Nahorski MS et al. Birt Hogg-Dube Syndrome-Associated FLCN MutationsDisrupt Protein Stability. Hum Mutat 2011; 32(8):921-929. Nickerson ML et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2002; 2(2):157-164.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000003529 SCV000883143 pathogenic Multiple fibrofolliculomas 2018-11-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003529 SCV001338245 pathogenic Multiple fibrofolliculomas 2020-02-05 criteria provided, single submitter clinical testing Variant summary: FLCN c.1285dupC (p.His429ProfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 245324 control chromosomes (gnomAD). c.1285dupC has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005, Hoshika_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant has an impact on protein function (Hoshika_2016). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000082626 SCV001450091 pathogenic not provided 2014-06-26 criteria provided, single submitter clinical testing
OMIM RCV000003529 SCV000023687 pathogenic Multiple fibrofolliculomas 2010-06-01 no assertion criteria provided literature only
OMIM RCV000003530 SCV000023688 pathogenic Pneumothorax, primary spontaneous 2010-06-01 no assertion criteria provided literature only
GeneReviews RCV000003529 SCV000041592 pathologic Multiple fibrofolliculomas 2008-09-09 no assertion criteria provided curation Converted during submission to Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082626 SCV000114668 pathogenic not provided 2013-04-11 no assertion criteria provided clinical testing

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