ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2051G>T (p.Cys684Phe) (rs1555399763)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659512 SCV000781337 likely pathogenic Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000702648 SCV000831510 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 684 of the FBN1 protein (p.Cys684Phe). 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 has been observed in an individual with clinical features of Marfan syndrome (Invitae). 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 being elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Variants that disrupt the p.Cys684 amino acid residue in FBN1 have been observed in affected individuals (PMID: 19293843, 18435798, 21932315). This suggest that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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