ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4747+5G>T

dbSNP: rs193922209
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000535198 SCV000627930 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-03-06 criteria provided, single submitter clinical testing This sequence change falls in intron 38 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 10189089, 27906200). ClinVar contains an entry for this variant (Variation ID: 457224). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in 38 (PMID: 10189089). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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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