ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1429C>T (p.Arg477Ter) (rs879255678)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239684 SCV000298083 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000256142 SCV000321667 pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing The R477X nonsense variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dube Syndrome (BHD) (Furuya et al., 2015; Schmidt et al., 2005). It has also been reported in a family with pneumothorax and blebs (Graham et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507127 SCV000603722 pathogenic not specified 2016-12-02 criteria provided, single submitter clinical testing
Invitae RCV000239684 SCV000632840 pathogenic Multiple fibrofolliculomas 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 477 (p.Arg477*) of the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with Birt-Hogg-Dubé syndrome (PMID: 15852235, 19457309, 24393238, 28558743, 20618353). This variant is also known as c.1884C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 253251). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000567617 SCV000673455 pathogenic Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing The p.R477* pathogenic mutation (also known as c.1429C>T), located in coding exon 9 of the FLCN gene, results from a C to T substitution at nucleotide position 1429. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in the literature in multiple individuals with clinical diagnoses of Birt-Hogg-Dubé (BHD) syndrome and primary spontaneous pneumothorax. Clinical findings reported in association with this mutation include BHD-associated cutaneous features, lung cysts, pneumothoraces, and renal cell carcinoma (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33; Graham RB et al. Am. J. Respir. Crit. Care Med. 2005 Jul; 172(1):39-44; Fuertes I et al. Actas Dermosifiliogr. 2009 Apr; 100(3):227-30; Maffé A et al. Clin. Genet. 2011 Apr; 79(4):345-54; Furuya M et al. Cancer Sci. 2015 Mar; 106(3):315-23; Liu Y et al. Orphanet J Rare Dis. 2017 May 30;12(1):104). Of note, this alteration is also designated as c.1884C>T, p.477R>X, and R477X in published literature. 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.
Fulgent Genetics,Fulgent Genetics RCV000762980 SCV000893425 pathogenic Multiple fibrofolliculomas; Pneumothorax, primary spontaneous; Potocki-Lupski syndrome; Carcinoma of colon; Renal cell carcinoma, nonpapillary 2018-10-31 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000256142 SCV001450356 pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing

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