ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1678G>A (p.Gly560Ser) (rs1064794283)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481478 SCV000568642 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN1 gene. The G560S variant has been previously reported in a three-year-old individual diagnosed with classic Marfan syndrome, fulfilling Ghent diagnostic criteria due to a positive family history, major ocular and cardiovascular system involvement and minor skeletal system involvement (Loeys et al., 2001). However, specific clinical details and segregation studies were not described for this individual. Nevertheless, the G560S variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, G560S 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. Furthermore, this substitution occurs within a calcium-binding (cb) EGF-like domain at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The G560S variant does not affect a Cysteine residue within a cb-EGF-like domain of the FBN1 gene, which is the most common mechanism of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003). However, this substitution does occur at a position in which Glycine is strongly conserved across different FBN1 cb-EGF-like domains, indicating it may be a structurally and/or functionally important residue. Furthermore, a missense variant at the same residue in the FBN1 gene (G560D) has been reported in association with Marfan syndrome (Baudhuin et al., 2015), however, the clinical significance of this variant also remains to be definitively determined.
Center for Medical Genetics Ghent,University of Ghent RCV000663480 SCV000786779 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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