Submissions for variant NM_144997.7(FLCN):c.1333G>A (p.Ala445Thr)

gnomAD frequency: 0.00217  dbSNP: rs41419545

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163302	SCV000213830	likely benign	Hereditary cancer-predisposing syndrome	2018-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121112	SCV000270205	likely benign	not specified	2015-08-06	criteria provided, single submitter	clinical testing	p.Ala445Thr in exon 12 of FLCN: This variant is not expected to have clinical si gnificance because it has been identified in 0.37% (246/66324) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs41419545). Additionally, 47 species including 27 mammals have a threon ine (Thr) at this position.
GeneDx	RCV000034789	SCV000278979	likely benign	not provided	2021-06-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22703879, 20522427, 21937013, 24728327, 19116017, 12843323, 29357828)
Invitae	RCV000232087	SCV000291431	benign	Birt-Hogg-Dube syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000232087	SCV000298080	likely benign	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000232087	SCV000400988	benign	Birt-Hogg-Dube syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000336471	SCV000400989	likely benign	Familial spontaneous pneumothorax	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034789	SCV000603723	likely benign	not provided	2021-08-30	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000232087	SCV000883142	uncertain significance	Birt-Hogg-Dube syndrome	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000232087	SCV001140310	likely benign	Birt-Hogg-Dube syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034789	SCV001151230	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FLCN: BP4, BS2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000232087	SCV001440532	likely benign	Birt-Hogg-Dube syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121112	SCV001467813	likely benign	not specified	2020-12-03	criteria provided, single submitter	clinical testing	Variant summary: FLCN c.1333G>A (p.Ala445Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 251048 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency greatly exceeds the estimated maximal expected allele frequency for a pathogenic variant in FLCN causing Birt-Hogg-Dube Syndrome phenotype (1.3e-06), strongly suggesting that the variant is benign. c.1333G>A has been reported in the literature in individuals affected with Birt-Hogg-Dube Syndrome (Kahnoski_2003), without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Birt-Hogg-Dube Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, 10 classify as likely benign/benign while 2 classify as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034789	SCV002009942	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121112	SCV002071745	likely benign	not specified	2021-11-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163302	SCV002530113	benign	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121112	SCV002551313	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121112	SCV002774734	benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232087	SCV004018701	benign	Birt-Hogg-Dube syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
OMIM	RCV000003537	SCV000023695	pathogenic	Carcinoma of colon	2003-07-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034789	SCV000043264	variant of unknown significance	not provided	2012-07-13	flagged submission	research	Converted during submission to Uncertain significance.
ITMI	RCV000121112	SCV000085280	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034789	SCV001741369	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034789	SCV001807195	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000034789	SCV001930835	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034789	SCV001954175	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034789	SCV001968054	likely benign	not provided		no assertion criteria provided	clinical testing