ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3012C>G (p.Tyr1004Ter) (rs397515784)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000035159 SCV000678237 pathogenic Marfan syndrome 2017-08-01 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon25 p.Tyr1004* (c.3012C>G): This variant has not been previously reported in the literature, but has been identified by our laboratory as de novo in 1 individual with a clinical suspicion of Marfan syndrome. This variant is not present in large control databases. This variant is present in ClinVar (Variant ID:42324). This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Dietz, PMID: 20301510). In summary, this variant is classified as pathogenic based on the predicted impact to the protein.
Center for Medical Genetics Ghent,University of Ghent RCV000035159 SCV000786911 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000610725 SCV000731217 pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
GeneDx RCV000627218 SCV000748206 pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing The Y1004X pathogenic variant in the FBN1 gene has been reported previously as a likely pathogenic variant in a 10-year-old boy with a history of severe internal carotid artery tortuosity, aortic dilatation, high arched palate, myopia, mild scoliosis and pectus carinatum (Lerner-Ellis et al., 2014). Additionally, one other clinical laboratory reported Y1004X as a de novo variant in a patient with clinical suspicion of Marfan syndrome (SCV000678237.1; Landrum et al., 2016). Furthermore, Y1004X has been seen to segregate with a Marfan-like phenotype in one other family undergoing Marfan/TAAD tested at GeneDx. Y1004X 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 Marfan syndrome (Stenson et al., 2014). Furthermore, the Y1004X variant is not observed in large population cohorts (Lek et al., 2016).In summary, Y1004X in the FBN1 gene is interpreted as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035159 SCV000058800 likely pathogenic Marfan syndrome 2008-03-01 criteria provided, single submitter clinical testing

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