ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5747G>A (p.Cys1916Tyr) (rs397515827)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781368 SCV000919347 uncertain significance not specified 2018-08-20 criteria provided, single submitter clinical testing Variant summary: FBN1 c.5747G>A (p.Cys1916Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245812 control chromosomes. c.5747G>A has been reported in the literature in individuals affected with MFS (Lerner-Ellis_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified a VUS - possibly pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035233 SCV000058878 likely pathogenic Marfan syndrome 2009-12-08 criteria provided, single submitter clinical testing

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