ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7039_7040del (p.Met2347fs) (rs794728319)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181674 SCV000233977 pathogenic not provided 2016-11-07 criteria provided, single submitter clinical testing The c.7039_7040delAT pathogenic variant in the FBN1 gene has previously been reported in individuals with suspected Marfan syndrome (MFS) or who met Ghent criteria for a diagnosis of MFS (Korkko et al., 2002; Comeglio et al., 2007; Howarth et al., 2007; Attanasio et al., 2008; Magyar et al., 2009; Yoo et al., 2010; Baudhuin et al.,2014; Somers et al., 2016), and in individuals with familial or sporadic TAAD (Regalado et al., 2015; Guo et al., 2015). Regalado et al. (2015) identified this variant in a 36 year-old male with type A aortic dissection, increased arm span to height ratio, a positive thumb sign, and a spontaneous pneumothorax and observed segregation of this variant with disease in this individual's brother, who had surgical repair of an aortic root aneurysm at 30 years-old. In addition, this variant has been identified in other unrelated individuals referred for Marfan/TAAD genetic testing at GeneDx and has been classified in ClinVar as a pathogenic variant by other clinical laboratories (ClinVar SCV000263920.1; SCV000283647.1; Landrum et al., 2016). This pathogenic variant causes a shift in reading frame starting at codon Methionine 2347 changing it to a Valine, and creating a premature stop codon at position 19 of the new reading frame, denoted p.Met2347ValfsX19. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the FBN1 gene have been reported in HGMD in association with MFS (Stenson et al., 2014). Furthermore, the c.7039_7040delAT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.7039_7040delAT in the FBN1 gene is interpreted as a pathogenic variant.
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 2020-10-18 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 58 of the FBN1 mRNA (c.7039_7040delAT), causing a frameshift at codon 2347. This creates a premature translational stop signal (p.Met2347Valfs*19) and is expected to result in an absent or disrupted protein product. Truncating variants in FBN1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals with Marfan syndrome (PMID: 11826022, 17618372, 17627385, 19618372) and thoracic aortic aneurysms and dissections (PMID: 26272055, 26621581). ClinVar contains an entry for this variant (Variation ID: 200171). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618779 SCV000738824 pathogenic Cardiovascular phenotype 2019-03-26 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 (K&ouml;rkk&ouml; 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; <span style="background-color:rgb(255, 255, 255)">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 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.
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 Familial thoracic aortic aneurysm; Acute aortic dissection 2016-01-20 no assertion criteria provided research

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