ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3373C>T (p.Arg1125Ter) (rs727505006)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770676 SCV000902138 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-03-30 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000156427 SCV000786957 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000578572 SCV000680524 pathogenic not provided 2018-06-27 criteria provided, single submitter clinical testing The R1125X variant in the FBN1 gene has been reported in multiple individuals with clinical features of Marfan syndrome (Rommel et al., 2005; Comeglio et al., 2007; Attanasio et al., 2008; Hung et al., 2009; Stheneur et al., 2009; Sheikhzadeh et al., 2012). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with FBN1-related disorders (Stenson et al., 2014). Furthermore, the R1125X variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000557569 SCV000627892 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-06-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1125*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in FBN1 are known to be pathogenic. This specific variant has been reported in individuals affected with Marfan syndrome (PMID: 16220557, 17657824, 19002209, 19839986, 23684891, 27011056). ClinVar contains an entry for this variant (Variation ID: 179632). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156427 SCV000206145 pathogenic Marfan syndrome 2014-03-06 criteria provided, single submitter clinical testing The Arg1125X variant in FBN1 has been reported in six individuals with clinical features of Marfan syndrome (Attanasio 2008, Comeglio 2007, Hung 2009, Rommel 20 05, Stheneur 2009, Sheikhzadeh 2012). This nonsense variant leads to a premature termination codon at position 1125, which is predicted to lead to a truncated o r absent protein. Heterozygous loss of function of the FBN1 gene is an establish ed disease mechanism in Marfan syndrome. In summary, this variant meets our crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM). The presenc e of a heterozygous pathogenic variant in FBN1 is consistent with a diagnosis of Marfan syndrome, but this information should be reconciled with the complete cl inical history of this individual.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000156427 SCV000740509 pathogenic Marfan syndrome 2016-11-26 criteria provided, single submitter clinical testing

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