ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7775G>T (p.Cys2592Phe) (rs112118237)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484944 SCV000573203 likely pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The C2592F likely pathogenic variant in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. C2592F is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C2592F 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2592F 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, a missense variant at the same residue (C2592S), and multiple missense variants in nearby residues (R2589G, C2590Y, G2595A, G2595S, Y2596C) have been reported in the Human Gene Mutation Database in association with Marfan syndrome/TAAD (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.
Integrated Genetics/Laboratory Corporation of America RCV000780264 SCV000917374 uncertain significance not specified 2017-12-22 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.7775G>T (p.Cys2592Phe) variant located in the EGF-like domain #41 involves the alteration of a conserved nucleotide affecting a Cysteine residue. The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992). Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. In further support, 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 245656 control chromosomes (gnomAD). In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Furthermore, a missense variant at this residue, Cys2592Ser, along with missense variants nearby, Arg2589Gly, Cys2590Tyr, Gly2595Ala, Gly2595Ser, and Tyr2596Cys, have been reported in affected individuals, therefore, suggesting the area is important for protein function. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Pathogenic."

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