ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5207G>A (p.Cys1736Tyr) (rs1060501070)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474273 SCV000544912 likely pathogenic Marfan syndrome 2016-10-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1736 of the FBN1 protein (p.Cys1736Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. 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). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, cysteine substitutions located in FBN1 TGFBP domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic.

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