ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7571-1G>A

dbSNP: rs1566891706
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000687633 SCV000815212 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-06-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 61 of the FBN1 gene. It is expected to disrupt RNA splicing and likely results 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 disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017716 SCV004847705 likely pathogenic Marfan syndrome 2019-04-17 criteria provided, single submitter clinical testing The c.7571-1G>A variant in FBN1 has not been previously reported in individuals with Marfan syndrome and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 567522). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In addition, the exon nearest this splice site includes one of the epidermal growth factor-like domains. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM1, PM2.

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