ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6453C>T (p.Cys2151=) (rs794728251)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505798 SCV000234003 likely pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing The c.6453 C>T (C2151C) likely pathogenic variant in the FBN1 gene has been reported in one Japanese patient andtwo relatives with diagnoses of Marfan syndrome (Ogawa et al., 2011). While this variant results in a synonymous amino acid substitution (C2151C), cDNA sequencing from affected aortic tissue revealed a truncatedmRNA product due to the creation of a new cryptic splice donor site (Ogawa et al., 2011). This strong cryptic splicedonor site is located upstream of the native splice donor site for intron 53. This variant is predicted to lead to eitheran abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if themessage is used for protein translation. Other downstream splice site variants in the FBN1 gene have been reported inHGMD in association with Marfan syndrome (Stenson et al., 2014). Additionally, the c.6453 C>T (C2151C) variantis not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000576722 SCV000678202 likely pathogenic Marfan syndrome 2017-08-01 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 53 p.Cys2151Cys (c.6453C>T): This variant has been reported in the literature in 1 individual with Marfan syndrome, segregating with disease in 2 affected relatives (Ogawa 2011 PMID:21907952). This variant is not present in large control databases. Although this is a ‘silent’ mutation, functional studies have demonstrated that this variant may result in a splice site alteration, resulting in an abnormal protein (Ogawa 2011 PMID:21907952). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Invitae RCV000631984 SCV000753087 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-11-15 criteria provided, single submitter clinical testing This sequence change affects codon 2151 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individuals and in a family affected with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 21907952, 26787436, Invitae). Experimental studies have shown that this silent change  affects protein splicing (PMID: 21907952). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000505798 SCV000885426 pathogenic not provided 2017-07-30 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000576722 SCV000787233 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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