ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4583-5A>G

dbSNP: rs778966916
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen RCV003235218 SCV003933713 likely pathogenic Marfan syndrome 2023-06-15 reviewed by expert panel curation The NM_000138.5 c.4583-5A>G variant in FBN1 is a variant in the splice acceptor region of intron 37. Computational splice prediction algorithms predict that this variant impacts splicing (PP3). This variant was identified in the literature and public databases in two individuals with clinical diagnoses of Marfan syndrome including once as de novo in an individual with phenotype consistent with but not highly specific to FBN1 and in an individual with aortic aneurysm and other features suggestive of Marfan syndrome; it was also found to segregate with disease in at least one affected family member (PS4_moderate, PM6_supporting; PMID: 25101912, Invitae internal data, ClinVar ID: 406332). It was also identified in a third individual with a clinical diagnosis of Marfan syndrome (PP4; Johns Hopkins). This variant is not present in gnomAD v2.1.1 or v3.1.2 (PM2_supporting; https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP (PS4_moderate, PM2_supporting, PM6_supporting, PP3, PP4).
Labcorp Genetics (formerly Invitae), Labcorp RCV000458795 SCV000544901 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-11-15 criteria provided, single submitter clinical testing This sequence change falls in intron 37 of the FBN1 mRNA. It does not directly change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (ExAC no frequency). This sequence change was reported as de novo in an individual affected with Marfan syndrome (PMID: 25101912, 25652356). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary this is a rare intronic variant that is predicted to affect protein splicing and has been reported as de novo in an affected individual. For these reasons, this variant has ben classified as Likely Pathogenic.

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