ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6772T>C (p.Cys2258Arg) (rs1057520617)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443127 SCV000516603 pathogenic not provided 2015-04-17 criteria provided, single submitter clinical testing The C2258R variant in the FBN1 gene has been previously reported in one individual with features ofMarfan syndrome, including ocular, skeletal, and cardiovascular features (Hayward C et al., 1997). Thissubstitution was absent from 120 control alleles without features of Marfan and identified in the proband's otheraffected relatives (Hayward et al., 1997). Furthermore, the C2258R variant was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The C2258R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. This substitution occurs at a position that is conservedacross species. In silico analysis predicts this variant is probably damaging to the protein structure/function.C2258R affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1, which may affectdisulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions inthe calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated withMarfan syndrome (Collod-Beroud et al., 2003). Additionally a missense variant in the same residue(C2258Y) and in nearby residues (C2265F, C2265Y) have been reported in HGMD in association with Marfansyndrome (Stenson P et al., 2014), further supporting the functional importance of this residue and region ofthe protein. In summary, C2258R in the FBN1 gene is interpreted as a pathogenic variant.
Center for Medical Genetics Ghent,University of Ghent RCV000663899 SCV000787265 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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