ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6113G>A (p.Cys2038Tyr) (rs363804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497640 SCV000589500 likely pathogenic not provided 2015-10-09 criteria provided, single submitter clinical testing The C2038Y variant that is likely pathogenic in the FBN1 gene has been reported previously in several unrelated individuals with Marfan syndrome or related features (Ng et al., 2002; Rommel et al., 2005; Sheikhzadeh et al., 2012). Rommel et al. (2005) reported that C2038Y was identified in one woman with Marfan syndrome and in two daughters with skeletal and cardiac features of Marfan syndrome but no ectopia lentis as seen in their mother. Sheikhzadeh et al. (2012) reported the C2038Y variant in one individual with suspected Marfan syndrome who did not meet Ghent criteria. The C2038Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C2038Y 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. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2038Y 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).Therefore, this variant is likely pathogenic
Center for Medical Genetics Ghent,University of Ghent RCV000663849 SCV000787207 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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