ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2446T>C (p.Cys816Arg)

dbSNP: rs1555399206
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001235910 SCV001408619 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-09-09 criteria provided, single submitter clinical testing This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals affected with Marfan syndrome (PMID: 18435798, Invitae). ClinVar contains an entry for this variant (Variation ID: 549084). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 816 of the FBN1 protein (p.Cys816Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Institute of Human Genetics, University Hospital Muenster RCV002287434 SCV002578029 pathogenic See cases 2022-09-29 criteria provided, single submitter clinical testing ACMG categories: PS3,PM1,PM2,PM5,PP3,PP5
GeneDx RCV003228974 SCV003926338 likely pathogenic not provided 2022-11-18 criteria provided, single submitter clinical testing Haplotype analysis demonstrates segregation with disease in affected individuals from a single family in published literature (Lledo et al., 2006); Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12938084, 10486319, 18435798, 17027361)
Center for Medical Genetics Ghent, University of Ghent RCV000663543 SCV000786854 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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