ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2T>G (p.Met1Arg)

dbSNP: rs886041536
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000362200 SCV000330209 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing The c.2 T>G pathogenic variant in the FBN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. As this pathogenic variant alters the translation initiator Methionine codon, the resultant protein is described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.2 T>G as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002519049 SCV003312254 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2024-09-28 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the FBN1 mRNA. The next in-frame methionine is located at codon 99. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 28973303, 29357934). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280307). 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). For these reasons, this variant has been classified as Pathogenic.

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