ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6997+4A>G

dbSNP: rs727503055
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000150697 SCV000198065 uncertain significance not specified 2016-02-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp RCV000232266 SCV000283646 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-10-26 criteria provided, single submitter clinical testing This sequence change falls in intron 57 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of FBN1-related conditions (PMID: 24793577; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 163464). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV003362691 SCV004078986 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-07-28 criteria provided, single submitter clinical testing The c.6997+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 56 in the FBN1 gene. This alteration has been reported in a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV004589641 SCV005079432 uncertain significance not provided 2023-10-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24793577)

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