ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7955G>A (p.Cys2652Tyr) (rs397515859)

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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 RCV000035283 SCV000058931 likely pathogenic Marfan syndrome 2009-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000181621 SCV000233924 likely pathogenic not provided 2018-03-30 criteria provided, single submitter clinical testing The C2652Y likely pathogenic variant in the FBN1 gene has been reported in at least one proband with a familial connective tissue disorder; this individual was described as having cardiovascular manifestations including aortic dilation, skeletal system involvement, and myopia (Turner et al., 2009). In addition, C2652Y was found in an affected relative, and it was absent in a second, unaffected relative (Howarth et al, 2007). Moreover, C2652Y is not observed in large population cohorts (Lek et al., 2016).The C2652Y variant results in a non-conservative amino acid substitution, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, C2652Y 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 FBN1-related disorders (Collod-Beroud et al., 2003).In summary, C2652Y in the FBN1 gene is interpreted as a likely pathogenic variant.

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