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

dbSNP: rs879255678

Total submissions: 11

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	Birt-Hogg-Dube syndrome	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239684	SCV000632840	pathogenic	Birt-Hogg-Dube syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg477*) in 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 (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 15852235, 19457309, 20618353, 24393238, 28558743). This variant is also known as c.1884C>T. 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	2024-05-07	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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Carcinoma of colon; Nonpapillary renal cell carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000256142	SCV001450356	pathogenic	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000239684	SCV004018068	pathogenic	Birt-Hogg-Dube syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000256142	SCV004219701	pathogenic	not provided	2023-06-18	criteria provided, single submitter	clinical testing	The FLCN c.1429C>T (p.Arg477*) variant causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in affected individuals and families with Burt-Hogg-Dube Syndrome (BHD) (PMIDs: 15805188 (2005), 15852235 (2005), 20618353 (2011), 24393238 (2014), 25594584 (2015), 28558743 (2017), 30360018 (2019), 32782288 (2020), 34148334 (2021), 34703430 (2021), and 35639097 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000256142	SCV005413176	pathogenic	not provided	2024-09-05	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000239684	SCV004032358	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing