ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4937G>A (p.Cys1646Tyr) (rs397515814)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035213 SCV000058858 likely pathogenic Marfan syndrome 2008-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000483918 SCV000568640 pathogenic not provided 2017-12-01 criteria provided, single submitter clinical testing The C1646Y pathogenic variant in the FBN1 gene has been reported in an adolescent male who fulfilled Ghent criteria for Marfan syndrome (Lerner-Ellis et al., 2014). Moreover, C1646Y appeared to be de novo in this affected male upon negative testing of both parents, although non-paternity was not ruled out (Lerner-Ellis et al., 2014). The C1646Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, the C1646Y variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Finally, the C1646Y variant is not observed in large population cohorts (Lek et al., 2016),

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