ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2055C>G (p.Cys685Trp)

dbSNP: rs140603
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000029703 SCV000058772 pathogenic Marfan syndrome 2007-04-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000631929 SCV000753032 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-06-08 criteria provided, single submitter clinical testing 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"). 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). For these reasons, this variant has been classified as Pathogenic.
Centre of Medical Genetics, University of Antwerp RCV000029703 SCV002025529 likely pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PS5, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
GenomeConnect - Invitae Patient Insights Network RCV003330401 SCV004037527 not provided Marfan syndrome; MASS syndrome; Stiff skin syndrome; Familial thoracic aortic aneurysm and aortic dissection no assertion provided phenotyping only Variant classified as Pathogenic and reported on 10-12-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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