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

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000082625	SCV000114667	pathogenic	not provided	2013-12-20	criteria provided, single submitter	clinical testing
UCLA Clinical Genomics Center, UCLA	RCV000003531	SCV000255372	pathogenic	Multiple fibrofolliculomas	2014-06-10	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000003531	SCV000298075	pathogenic	Multiple fibrofolliculomas	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082625	SCV000321665	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	The c.1285delC variant in the FLCN gene has been previously reported in association with Birt-Hogg-Dube syndrome (for examples, see Khoo et al., 2002; Fontcuberta et al., 2011; Benusiglio et al., 2014; Jensen et al., 2017). This deletion causes a frameshift starting with codon Histidine 429, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 39 of the new reading frame, denoted p.His429ThrfsX39. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.1285delC to be pathogenic.
Invitae	RCV000003531	SCV000549477	pathogenic	Multiple fibrofolliculomas	2020-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His429Thrfs*39) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80338683, ExAC 0.04%). This variant has been reported in individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 20301695, 25519458, 12471204, 25827758). This variant is also known as c.1733delC in the literature. ClinVar contains an entry for this variant (Variation ID: 3364). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492709	SCV000580727	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-06	criteria provided, single submitter	clinical testing	The c.1285delC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1285, causing a translational frameshift with a predicted alternate stop codon (p.H429Tfs*39). This mutation has been reported in the literature in multiple individuals with features consistent with Birt-Hogg-Dubé​ syndrome, including fibrofolliculomas, spontaneous pneumothorax, lung cysts, benign renal cysts, and renal tumors (Khoo SK et al. J. Med. Genet. 2002 Dec;39:906-12; Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Whitworth J et al. JAMA Oncol. 2016 Mar;2:373-9; Rossing M et al. J. Hum. Genet. 2017 Feb;62:151-157). Of note, this alteration is also designated as c.1733delC 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001000611	SCV001157602	pathogenic	not specified	2019-05-14	criteria provided, single submitter	clinical testing	The FLCN c.1285delC; p.His429fs variant (rs80338683), also known as 1733delC, is reported in several individuals and families with Birt-Hogg-Dube syndrome (Khoo 2002, Ray 2015, Whitworth 2016, Xing 2017), and is reported as pathogenic in ClinVar (Variation ID: 3364). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Khoo SK et al. Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet. 2002 Dec;39(12):906-12. Ray A et al. Genetic analysis of familial spontaneous pneumothorax in an Indian family. Lung. 2015 Jun;193(3):433-8. Whitworth J et al. Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA Oncol. 2016 Mar;2(3):373-9. Xing H et al. Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax. J Thorac Dis. 2017 Jul;9(7):1967-1972.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000082625	SCV001450180	pathogenic	not provided	2016-01-19	criteria provided, single submitter	clinical testing
OMIM	RCV000003531	SCV000023689	pathogenic	Multiple fibrofolliculomas	2009-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000003531	SCV000041591	pathologic	Multiple fibrofolliculomas	2008-09-09	no assertion criteria provided	curation	Converted during submission to Pathogenic.