ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2495G>A (p.Cys832Tyr) (rs397515775)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035145 SCV000058786 likely pathogenic Marfan syndrome 2008-06-04 criteria provided, single submitter clinical testing
GeneDx RCV000427032 SCV000516936 pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing The C832Y variant in the FBN1 gene has been reported in several unrelated individuals with Marfansyndrome and was absent from 160 control alleles (Liu et al., 1997; Schrijver et al., 1999; Arbustini et al., 2005; Comeglio et al., 2007). Additionally, the C832Y substitution 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. C832Y results in a non-conservative amino acid substitution at a position that is conserved across species. Consequently, in silico analysis predicts C832Y is probably damaging to the protein structure/function. Furthermore, the C832Y variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, and affects C5-C6 disulfide bonding and is predicted to alter the structure and function of the protein (Schrijver et al., 1999). 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). Moreover, a missense variant in the same residue (C832F) and variants in nearby residues (F828C, C830S, C830Y, L838S) have been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. In summary, C832Y in FBN1 is interpreted as a pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000035145 SCV000839956 pathogenic Marfan syndrome 2018-04-03 criteria provided, single submitter clinical testing This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene has been reported in multiple unrelated individuals with Marfan syndrome (PMID: 10464652, 16222657, 17657824) and is extremely rare in the general population. Other reports have also observed different changes at the same amino acid in patients with Marfan syndrome (PMID: 19839986, 24793577). There is also strong functional data supporting pathogenesis (PMID: 10486319, 10464652). This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene is classified as pathogenic.

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