ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7039_7040del (p.Met2347fs)

dbSNP: rs794728319
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181674 SCV000233977 pathogenic not provided 2022-04-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29357934, 11826022, 25101912, 27112580, 17627385, 19863550, 26272055, 17657824, 19618372, 18435798, 29543232, 33436942, 32679894, 34008892, 26621581)
Blueprint Genetics RCV000208062 SCV000263920 pathogenic Marfan syndrome 2015-08-21 criteria provided, single submitter clinical testing
Invitae RCV000524503 SCV000283647 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met2347Valfs*19) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 11826022, 17627385, 19618372, 26272055, 26621581). ClinVar contains an entry for this variant (Variation ID: 200171). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000613882 SCV000738824 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2022-07-07 criteria provided, single submitter clinical testing The c.7039_7040delAT pathogenic mutation, located in coding exon 57 of the FBN1 gene, results from a deletion of two nucleotides at nucleotide positions 7039 to 7040, causing a translational frameshift with a predicted alternate stop codon (p.M2347Vfs*19). This alteration has been described in multiple individuals with Marfan syndrome or related phenotypes (Körkkö J et al. J Med Genet. 2002 ;39:34-41; Howarth R et al. Genet Test. 2007;11:146-52; Comeglio P et al. Hum Mutat. 2007;28:928; Attanasio M et al. Clin Genet. 2008 ;74:39-46; Magyar I et al. Hum Mutat. 2009;30:1355-64; Yoo EH et al. Clin Genet. 2010;77:177-82; Regalado ES et al. Clin Genet. 2016 ;89:719-23; Guo J et al. Sci Rep. 2015;5:13115; Somers AE et al. Am J Med Genet A. 2016;170:1786-90). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000208062 SCV000781410 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000181674 SCV000885431 pathogenic not provided 2017-09-16 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000208062 SCV000928336 pathogenic Marfan syndrome 2018-01-04 criteria provided, single submitter clinical testing PVS1, PM2, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192804 SCV001361164 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2019-02-25 criteria provided, single submitter clinical testing Variant summary: FBN1 c.7039_7040delAT (p.Met2347ValfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245612 control chromosomes (gnomAD). c.7039_7040delAT has been reported in the literature in multiple individuals affected with Marfan Syndrome (Korkko_2002, Attanasio_2008, Comeglio_2007, Yoo_2010, Baudhuin_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratoire Génétique Moléculaire, CHRU TOURS RCV000181674 SCV001760720 pathogenic not provided 2020-09-23 criteria provided, single submitter clinical testing
3billion RCV001775090 SCV002012050 pathogenic Weill-Marchesani syndrome 2, dominant 2021-10-02 criteria provided, single submitter clinical testing Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000200171.11). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centre of Medical Genetics, University of Antwerp RCV000208062 SCV002025431 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS1, PP4 or PM2, PVS1, PP1, PP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000613882 SCV002042012 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-05-14 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV000208062 SCV002577937 pathogenic Marfan syndrome 2021-12-20 criteria provided, single submitter clinical testing ACMG categories: PVS1,PP3,PP5
Lifecell International Pvt. Ltd RCV000208062 SCV003924076 pathogenic Marfan syndrome criteria provided, single submitter clinical testing A Heterozygous Frameshift variant c.7039_7040delAT in Exon 58 of the FBN1 gene that results in the amino acid substitution p.Met2347fs*19 was identified. The observed variant novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 200171). This variant has previously been reported for Marfan syndrome (Comeglio P et al., 2007). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Centre for Genomic and Experimental Medicine, University of Edinburgh RCV000613882 SCV000731223 pathogenic Familial thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Center for Medical Genetics Ghent, University of Ghent RCV000208062 SCV000787293 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Center for Medical Genetics Ghent, University of Ghent RCV000208062 SCV000787294 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV000755190 SCV000883019 likely pathogenic Congenital aneurysm of ascending aorta; Acute aortic dissection 2016-01-20 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.