ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1916G>A (p.Cys639Tyr) (rs878853676)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229819 SCV000283608 likely pathogenic Marfan syndrome 2016-02-14 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 639 of the FBN1 protein (p.Cys639Tyr). 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). This variant has been reported to segregate with Marfan or Marfan-like syndrome in a single family (PMID: 17627385). In addition, this variant has been observed in unrelated individuals with Marfan syndrome (PMID: 12938084, 21895641) and isolated ectopia lentis (PMID: 25053872). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In addition, this variant is located in an EGF-like domain of the FBN1 protein and affects a cysteine (p.Cys639) that is suggested to be involved in the formation of a disulfide bridge that is critical for protein folding (PMID: 3282918, 3495735, 4750422, 16677079). In summary, this variant is absent from population databases, has been observed in several individuals with Marfan syndrome, and is predicted to be deleterious. In the absence of additional confirmed segregation evidence, at this time this variant has been classified as Likely Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000229819 SCV000786810 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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