Submissions for variant NM_144997.7(FLCN):c.1318_1334dup (p.Leu449fs)

dbSNP: rs879255677

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239636	SCV000298079	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000483674	SCV000565010	pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing	The c.1318_1334dup17 variant in the FLCN gene has not been reported previously as a pathogenicvariant, nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codonLeucine 449, changes this amino acid to a Glutamine residue and creates a premature Stop codon atposition 25 of the new reading frame, denoted p.Leu449GlnfsX25. The c.1318_1334dup17 variant ispredicted to cause loss of normal protein function either through protein truncation or nonsensemediatedmRNA decay. Based on currently available evidence, we consider c.1318_1334dup17 to bepathogenic, and its presence consistent with a diagnosis of Birt-Hogg-Dube syndrome.
Ambry Genetics	RCV000492447	SCV000580743	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The c.1318_1334dup17 variant, located in coding exon 9 of the FLCN gene, results from a duplication of GAGGTCCACGCAGCCGC at nucleotide position 1318, causing a translational frameshift with a predicted alternate stop codon (p.L449Qfs*25). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239636	SCV000947110	pathogenic	Birt-Hogg-Dube syndrome	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu449Glnfs*25) 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 renal cell carcinoma (PMID: 18794106, 19802896). This variant is also known as c.1833_1849dup17. ClinVar contains an entry for this variant (Variation ID: 253249). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786636	SCV002768451	pathogenic	Birt-Hogg-Dube syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Birt-Hogg-Dube syndrome (BHDS) (MIM#135150) and primary spontaneous pneumothorax (MIM#173600). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have intra- and inter-familial variable expressivity (OMIM; PMID: 15852235; 30586397). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in association with BHDS and hereditary cancer predisposing syndrome (ClinVar), as well as in four BHDS families in a conference abstract with limited information (PMID: 21506000). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Myriad Genetics, Inc.	RCV000239636	SCV004188952	pathogenic	Birt-Hogg-Dube syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483674	SCV004218925	pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	The FLCN c.1318_1334dup (p.Leu449Glnfs*25) variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in an individual with renal cell carcinoma (PMID: 18794106 (2008)). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000483674	SCV004564596	pathogenic	not provided	2023-11-11	criteria provided, single submitter	clinical testing	The FLCN c.1318_1334dup; p.Leu449GlnfsTer25 variant (rs879255677) is reported in the literature in at least one individual with a Birt-Hogg-Dube-associated phenotype (Savatt 2022). This variant is also reported in ClinVar (Variation ID: 253249). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting 17 nucleotides, 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: Savatt JM et al. Frequency of truncating FLCN variants and Birt-Hogg-Dube-associated phenotypes in a health care system population. Genet Med. 2022 Sep;24(9):1857-1866. PMID: 35639097.
Mayo Clinic Laboratories, Mayo Clinic	RCV000483674	SCV005413177	likely pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	PM2_moderate, PVS1