ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4243dup (p.Cys1415fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001255474 SCV001431891 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2020-08-10 criteria provided, single submitter clinical testing Variant summary: FBN1 c.4243dupT (p.Cys1415LeufsX16) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251416 control chromosomes. To our knowledge, no occurrence of c.4243dupT in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286111 SCV001472637 pathogenic none provided 2019-10-28 criteria provided, single submitter clinical testing The FBN1 c.4243dupT; p.Cys1415fs variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, a number of downstream truncating variants have been described in association with Marfan syndrome and are considered pathogenic (Stheneur 2009). Based on available information, the p.Cys1415fs variant is considered to be pathogenic. References: Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8.

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