Submissions for variant NM_144997.7(FLCN):c.779+1G>T

gnomAD frequency: 0.00001  dbSNP: rs758175953

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218992	SCV000275068	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-07	criteria provided, single submitter	clinical testing	The c.779+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the FLCN gene. This mutation has been reported in multiple individuals/families with Birt-Hogg-Dube syndrome (Toro JR et al. J. Med. Genet. 2008 Jun; 45(6):321-31; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239675	SCV000298060	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000255322	SCV000321657	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 18234728, 21937013, 19802896, 29357828, 33726816, 23050938, 35176117)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506237	SCV000603727	pathogenic	not specified	2017-01-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239675	SCV000632890	pathogenic	Birt-Hogg-Dube syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the FLCN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs758175953, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with Birt–Hogg–Dubé syndrome (PMID: 18234728, 21937013, 23050938). This variant is also known as IVS7+1 G>T. ClinVar contains an entry for this variant (Variation ID: 231274). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762981	SCV000893426	likely 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
Myriad Genetics, Inc.	RCV000239675	SCV004045393	pathogenic	Birt-Hogg-Dube syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35176117, 18234728, 23050938].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255322	SCV004219730	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal FLCN mRNA splicing. The frequency of this variant in the general population, 0.000039 (5/129096 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 18234728 (2008), 21937013 (2012), 23050938 (2012), 35176117 (2022)). Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255322	SCV004227706	pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PS4_moderate, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255322	SCV004242774	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255322	SCV005197949	pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000239675	SCV004032405	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing