ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2055C>G (p.Cys685Trp) (rs140603)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000029703 SCV000058772 pathogenic Marfan syndrome 2007-04-24 criteria provided, single submitter clinical testing
Invitae RCV000631929 SCV000753032 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 685 of the FBN1 protein (p.Cys685Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Marfan syndrome or an aortopathy (PMID: 21542060, 12203992, 15241795, 27611364). ClinVar contains an entry for this variant (Variation ID: 36043). This variant affects a cysteine residue located within a TGFBP domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and to be important for FBN1 structure. Although the exact function of the FBN1 TGFBP domains has not being elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000029703 SCV000052356 pathogenic Marfan syndrome 2015-04-08 no assertion criteria provided clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000029703 SCV000786823 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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