ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5874C>A (p.Cys1958Ter) (rs1555395750)

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Total submissions: 3
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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 RCV000588466 SCV000695570 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-05-10 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.5874C>A (p.Cys1958*) variant results in a premature termination codon and predicted to cause a truncated or absent FBN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121166 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor was evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002491 SCV001160444 pathogenic not specified 2019-03-29 criteria provided, single submitter clinical testing The FBN1 c.5874C>A; p.Cys1958Ter variant, to our knowledge, has not been described in the medical literature but contains an entry in ClinVar (Variation ID: 495630). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in association with Marfan syndrome and are considered pathogenic (Stheneur 2009). Based on available information, the p.Cys1958Ter variant is considered 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.
Invitae RCV001390032 SCV001591602 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-05-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys1958*) 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). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 495630). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). For these reasons, this variant has been classified as Pathogenic.

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