ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1333G>A (p.Ala445Thr) (rs41419545)

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Total submissions: 20
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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 In silico models in agreement (benign);Other strong data supporting benign classification
Laboratory for Molecular Medicine, Partners HealthCare 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 Multiple fibrofolliculomas 2020-12-08 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000232087 SCV000298080 likely benign Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000232087 SCV000400988 benign Multiple fibrofolliculomas 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 Clinical Services Laboratory,Illumina RCV000336471 SCV000400989 likely benign Pneumothorax, primary spontaneous 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 RCV001281816 SCV000603723 likely benign none provided 2020-05-05 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000232087 SCV000883142 uncertain significance Multiple fibrofolliculomas 2018-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000232087 SCV001140310 likely benign Multiple fibrofolliculomas 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034789 SCV001151230 likely benign not provided 2021-03-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000232087 SCV001440532 likely benign Multiple fibrofolliculomas 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.
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 no assertion criteria provided 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
Human Genetics - Radboudumc,Radboudumc RCV000034789 SCV001954175 likely benign not provided no assertion criteria provided clinical testing

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