Submissions for variant NM_144997.7(FLCN):c.779G>A (p.Trp260Ter)

dbSNP: rs368778627

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635567	SCV000756985	pathogenic	Birt-Hogg-Dube syndrome	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp260*) 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 present in population databases (rs368778627, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 18579543, 22068306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161246). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000635567	SCV002073130	pathogenic	Birt-Hogg-Dube syndrome		criteria provided, single submitter	clinical testing	The stop gained p.W260* in FLCN (NM_144997.7) has been reported previously in families with Birt-Hogg-Dube syndrome (Frohlich BA et al; Sattler EC et al). The variant has been submitted to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic
Ambry Genetics	RCV002408655	SCV002673291	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	The p.W260* pathogenic mutation (also known as c.779G>A), located in coding exon 4 of the FLCN gene, results from a G to A substitution at nucleotide position 779. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. This variant has been shown to co-segregate with disease in two families in the literature (Fröhlich BA et al. Eur. Respir. J., 2008 Nov;32:1316-20; Sattler EC et al. Acta Derm. Venereol., 2012 Mar;92:187-8). 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.
Myriad Genetics, Inc.	RCV000635567	SCV003806642	pathogenic	Birt-Hogg-Dube syndrome	2023-01-18	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	RCV004567166	SCV005058668	pathogenic	Birt-Hogg-Dube syndrome 1	2024-03-15	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV004567166	SCV005382106	pathogenic	Birt-Hogg-Dube syndrome 1	2024-10-17	criteria provided, single submitter	clinical testing	ACMG Criteria: PP5, PM2_P, PS1_M, PVS1; Variant was found in heterozygous state
CSER _CC_NCGL, University of Washington	RCV000148502	SCV000190213	pathogenic	Familial spontaneous pneumothorax	2014-06-01	no assertion criteria provided	research