Submissions for variant NM_144997.7(FLCN):c.1522_1524del (p.Lys508del)

gnomAD frequency: 0.00001  dbSNP: rs398124529

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082629	SCV000114671	pathogenic	not provided	2013-07-11	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239713	SCV000298087	likely pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082629	SCV000321670	pathogenic	not provided	2019-12-23	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: impaired folliculin stability (Nahorski 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 19659657, 27220747, 30873309, 23364595, 30632664, 27229674, 21538689)
Invitae	RCV000239713	SCV000937134	pathogenic	Birt-Hogg-Dube syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This variant, c.1522_1524del, results in the deletion of 1 amino acid(s) of the FLCN protein (p.Lys508del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398124529, gnomAD 0.003%). This variant has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 19659657, 23364595; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96477). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FLCN function (PMID: 21538689). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000082629	SCV001502227	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390247	SCV002705330	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-31	criteria provided, single submitter	clinical testing	The c.1522_1524delAAG pathogenic mutation (also known as p.K508del) is located in coding exon 10 of the FLCN gene. This pathogenic mutation results from an in-frame AAG deletion at nucleotide positions 1522 to 1524. This results in the in-frame deletion of a lysine at codon 508. This variant has been reported in multiple individuals with a clinical diagnosis of Birt-Hogg-Dube syndrome (So SY et al. Respirology. 2009 Jul;14:775-6; Furuya M et al. Clin. Genet. 2016 Nov;90:403-412; Tarafdar S and Gleadle JM. Kidney Int. 2013 Feb;83(2):337-8; Radzikowska E et al. Orphanet J Rare Dis, 2021 07;16:302; Ambry internal data). In addition, functional studies have reported impaired stability and nuclear localization for this variant (Nahorski MS et al. Hum. Mutat. 2011 Aug;32:921-9; Clausen L et al. PLoS Genet, 2020 11;16:e1009187). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003398684	SCV004105513	pathogenic	FLCN-related condition	2023-08-04	criteria provided, single submitter	clinical testing	The FLCN c.1522_1524delAAG variant is predicted to result in an in-frame deletion (p.Lys508del). This variant has been reported in individuals with Birt-Hogg-Dubé syndrome, including affected family members (So et al. 2009. PubMed ID: 19659657; Radzikowska et al. 2021. PubMed ID: 34229741; Furuya et al. 2016. PubMed ID: 27220747; Tarafdar et al. 2013. PubMed ID: 23364595). Functional studies support this variant's pathogenicity (Clausen et al. 2020. PubMed ID: 33137092; Nahorski et al. 2011. PubMed ID: 21538689). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (one heterozygous allele, http://gnomad.broadinstitute.org/variant/17-17118312-CCTT-C). This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000239713	SCV004188019	likely pathogenic	Birt-Hogg-Dube syndrome	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33137092, 21538689]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34229741, 23364595, 19659657, 27220747, 33313181].
Mayo Clinic Laboratories, Mayo Clinic	RCV000082629	SCV004226810	likely pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	PP4, PM2, PM4, PS3_supporting, PS4_moderate
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV000239713	SCV004032362	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing