ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.266G>A (p.Cys89Tyr) (rs112660651)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620065 SCV000738839 pathogenic Cardiovascular phenotype 2016-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Center for Medical Genetics Ghent,University of Ghent RCV000663567 SCV000786878 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000181643 SCV000233946 likely pathogenic not provided 2016-11-14 criteria provided, single submitter clinical testing The C89Y variant in the FBN1 gene has been reported previously in association with Marfan syndrome (Tjedlhorn et al., 2006; Rand-Hendriksen et al., 2007; Stheneur et al., 2009; Proost et al., 2015). This 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 C89Y 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C89F, C89W) have been reported in HGMD in association with Marfan syndrome (Stenson et al., 2009), however, the pathogenicity of these variants has not been definitively determined.Therefore, this variant is a strong candidate for a pathogenic variant, however, the possibility that it is a benign variant cannot be excluded.
Invitae RCV000539344 SCV000627862 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-06-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 89 of the FBN1 protein (p.Cys89Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency) . This  variant has been reported in individuals with Marfan syndrome, including an individual where the variant was reported to arise de novo (PMID: 17253931, 19293843, 19720936), and has been reported in individuals in the Universal Mutation Database (PMID: 12938084). ClinVar contains an entry for this variant (Variation ID: 200141). This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). A different missense substitution at this codon (p.Cys89Phe) has also been  determined to be pathogenic (PMID: 11700157, 11810645, 19293843). This suggests that this cysteine residue is critical for FBN1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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