Submissions for variant NM_144997.7(FLCN):c.1389C>G (p.Tyr463Ter)

dbSNP: rs137852929

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166580	SCV000217382	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-22	criteria provided, single submitter	clinical testing	The p.Y463* pathogenic mutation (also known as c.1389C>G), located in coding exon 9 of the FLCN gene, results from a C to G substitution at nucleotide position 1389. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals with Birt-Hogg-Dubé syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76(6):1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45(6):321-31), including one large family where the mutation co-segregated with disease in six of six affected individuals (Nickerson ML et al. Cancer Cell. 2002 Aug;2(2):157-64). 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000003534	SCV000298081	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000255586	SCV000321666	pathogenic	not provided	2021-12-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as c.1844C>G; This variant is associated with the following publications: (PMID: 19802896, 15852235, 18234728, 23784378, 25525159, 25126726, 28869776, 19562744, 29357828, 31008171, 12204536)
Invitae	RCV000003534	SCV000549459	pathogenic	Birt-Hogg-Dube syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr463*) 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: 12204536, 15852235, 18234728). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3367). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781382	SCV000919361	pathogenic	Familial spontaneous pneumothorax	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The FLCN c.1389C>G (p.Tyr463X) variant results in a premature termination codon, predicted to cause a truncated or absent FLCN protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. One functional study showed increased interaction with the autophagy kinase ULK1 with this variant as well as impaired binding to the GABA(A) receptor-associated protein and higher levels of sequestome 1 (SQSTM1)( Dunlop_FLCN_Autophagy_2014). This variant is absent in 246200 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. This variant was found in multiple patients with Birt-Hogg-Dube syndrome (Schmidt_FLCN_2005). Taken together, this variant is classified as pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000003534	SCV001761634	pathogenic	Birt-Hogg-Dube syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The FLCN c.1389C>G (p.Tyr463Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant has been reported in several families with Birt-Hogg-Dubé syndrome (PS4; PMID: 12204536, 15852235, 18234728), including one large family where the mutation co-segregated with disease in six of six affected individuals (PP1; PMID: 12204536). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting, PP1.
Myriad Genetics, Inc.	RCV000003534	SCV004188097	pathogenic	Birt-Hogg-Dube syndrome	2023-07-07	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.
Baylor Genetics	RCV000003534	SCV004199793	pathogenic	Birt-Hogg-Dube syndrome	2023-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255586	SCV004218929	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of FLCN protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with Birt-Hogg-Dube (BHD) syndrome (PMID: 12204536 (2002), 15852235 (2005), 18234728 (2008), and 23784378 (2013)). Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255586	SCV004226832	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PM2, PVS1
PreventionGenetics, part of Exact Sciences	RCV003914800	SCV004729040	pathogenic	FLCN-related condition	2024-01-04	criteria provided, single submitter	clinical testing	The FLCN c.1389C>G variant is predicted to result in premature protein termination (p.Tyr463*). This variant has been reported in individuals with Birt-Hogg-Dube Syndrome (Nickerson et al. 2002. PubMed ID: 12204536; Toro et al. 2008. PubMed ID: 18234728; Pithadia et al. 2019. PubMed ID: 31008171). It is also known in the literature as c.1844C>G. This variant has not been reported in a large population database and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3367/). Nonsense variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000003534	SCV000023692	pathogenic	Birt-Hogg-Dube syndrome	2009-09-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000003534	SCV002075192	not provided	Birt-Hogg-Dube syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-28-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.