ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2087G>T (p.Cys696Phe)

dbSNP: rs1566913685
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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 RCV000705083 SCV000834063 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-03-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 696 of the FBN1 protein (p.Cys696Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant affects a cysteine residue located within a TGFBP domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and to be important for FBN1 structure. Although the exact function of the FBN1 TGFBP domains has not been elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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