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

dbSNP: rs1555399206

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001235910	SCV001408619	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2019-09-09	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Marfan syndrome (PMID: 18435798, Invitae). ClinVar contains an entry for this variant (Variation ID: 549084). 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. For these reasons, this variant has been classified as Pathogenic. 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).
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)
Neuberg Centre For Genomic Medicine, NCGM	RCV000663543	SCV005438756	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	The observed missense variant c.2446T>Cp.Cys816Arg in FBN1 gene has been reported previously in individuals with Marfan syndrome. 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 Attanasio M, et al., 2008; Ono RN, et al., 2009. This variant is present in a mutational hotspot. Different amino acid changes p.Cys816Tyr, p.Cys816Trp affecting teh same codon have been previously reported as pathogenic Stheneur C, et al., 2009; Lerner-Ellis JP, et al., 2014. This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Cys at position 816 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663543	SCV000786854	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing