ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2728+1G>C (rs794728322)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181678 SCV000233981 pathogenic not provided 2014-09-29 criteria provided, single submitter clinical testing c.2728+1 G>C: IVS23+1 G>C in intron 23 of the FBN1 gene (NM_000138.4) Although the FBN1 mutation has not been reported as a disease- causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 23 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the FBN1 gene have been reported in association with Marfan syndrome. In summary, c.2728+1 G>C in the FBN1 gene is interpreted as a disease-causing mutation.The variant is found in TAAD panel(s).
Invitae RCV000705129 SCV000834112 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-03-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 23 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. ClinVar contains an entry for this variant (Variation ID: 200174). 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. A different variant affecting this nucleotide (c.2728+1G>A) has been reported in individuals with Marfan syndrome (PMID: 19293843, 22772377). 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.

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