ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6661T>C (p.Cys2221Arg) (rs113543334)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507361 SCV000603648 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing The p.Cys2221Arg variant has been previously reported in associated with Marfan syndrome and in vitro functional studies demonstrated that the p.Cys2221Arg variant impairs fibrillin deposition (Schrijver 1999). This variant occurs in a cysteine residue in one of the EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768212 SCV000898688 likely pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-12-01 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 55 p.Cys2221Arg (c.6661T>C): This variant has been reported in the literature in at least 3 individuals with suspected Marfan syndrome, segregating with disease in 2 affected family members (Schrijver 1999 PMID:10486319, Matsukawa 2001 PMID:1139245, Attanasio 2008 PMID:18435798). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID: 439708). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Functional studies also suggest that this variant may impact the protein (Schrijver 1999 PMID:10486319). Of note, this variant is predicted to affect a cysteine residue. Cysteine in the FBN1 gene is reported to have important functional relevance; variants that involve a cysteine residue are reported to be particularly significant (Dietz 1992 PMID:1301946). In addition, several other variants (p.Cys2221Gly, p.Cys2221Phe, p.Cys2221Tyr) at this position have been reported in individuals with Marfan syndrome, supporting the potential functional relevance of this codon. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Invitae RCV000806890 SCV000946911 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 2221 of the FBN1 protein (p.Cys2221Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Marfan syndrome and observed to segregate with Marfan syndrome in a family (PMID: 10486319, 11139245). ClinVar contains an entry for this variant (Variation ID: 439708). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Experimental studies have shown that this missense change results in reduced fibrillin-1 secretion (PMID: 10486319). For these reasons, this variant has been classified as Pathogenic.

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