ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5918-2A>G

dbSNP: rs869025418
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208432 SCV000263916 likely pathogenic Marfan syndrome 2015-11-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000532804 SCV000627946 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2025-01-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 48 of the FBN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of FBN1-related conditions (PMID: 16220557, 20564469; internal data). ClinVar contains an entry for this variant (Variation ID: 222617). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002354586 SCV002653340 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-08-09 criteria provided, single submitter clinical testing The c.5918-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 48 in the FBN1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV004696873 SCV005197873 likely pathogenic not provided 2022-07-07 criteria provided, single submitter clinical testing

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