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

Total submissions: 9

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
Division of Genomic Diagnostics,The 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	2019-12-05	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-Dub 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	Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.
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.