ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4567C>T (p.Arg1523Ter) (rs397515812)

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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 RCV000770665 SCV000902124 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2017-10-02 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000035205 SCV000781374 pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000035205 SCV000787077 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000579083 SCV000680640 pathogenic not provided 2018-01-05 criteria provided, single submitter clinical testing The R1523X variant in the FBN1 gene has been reported previously in at least three unrelated individuals with Marfan syndrome (Youil et al., 2000; Schrijver et al., 2002; Baudhuin et al., 2014). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense pathogenic variants in the FBN1 gene have been reported in HGMD in association with FBN1-related disorders (Stenson et al., 2014). The R1523X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R1523X as a pathogenic variant.
Invitae RCV000539432 SCV000627921 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-05-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1523*) 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 particular variant has been reported in two individuals affected with a FBN1-related disease (PMID: 10874320, 12068374). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035205 SCV000058848 pathogenic Marfan syndrome 2018-04-20 criteria provided, single submitter clinical testing The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, Soylen 2009, Youil 2000, LMM data) and has also been reported by other cl inical laboratories in ClinVar (Variation ID: 42365). It has been identified in 1/245856 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397515812). This nonsense variant leads to a prematur e termination codon at position 1523, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an establis hed disease mechanism in individuals with Marfan syndrome. In summary, this vari ant meets criteria to be classified as pathogenic for Marfan syndrome in an auto somal dominant manner based upon presence in multiple affected individuals and t he predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS4.

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