Submissions for variant NM_000138.5(FBN1):c.184C>T (p.Arg62Cys)

dbSNP: rs25403

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035129	SCV000058769	pathogenic	Marfan syndrome	2006-10-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000493952	SCV000582883	pathogenic	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Identified primarily in patients with isolated ectopia lentis (EL) in published literature (Korkko et al., 2002; Katzke et al., 2002; Ades et al., 2004; Yu et al., 2006; Zhao et al., 2013; Wooderchak-Donahue et al., 2015; Stark et al., 2020; Chen et al., 2021; Zhou et al., 2021) and in patients referred for genetic testing at GeneDx; Identified in a patient with bilateral ectopia lentis, aortic dilation, and arachnodactyly (Katze et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; 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); Arginine (R) to cysteine (C) changes in the FBN1 are suspected to be predominantly associated with isolated EL (Jin et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11826022, 18079676, 15054843, 27611364, 25944730, 16765689, 22950452, 32123317, 12203987, 12203992, 17679947, 32679894, 34281902, 33576469)
Ambry Genetics	RCV002313727	SCV000738849	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-02-26	criteria provided, single submitter	clinical testing	The p.R62C pathogenic mutation (also known as c.184C>T), located in coding exon 2 of the FBN1 gene, results from a C to T substitution at nucleotide position 184. The arginine at codon 62 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the 4-cys motif LTBP-like domain near the cb EGF-like #01 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This alteration has been reported in several patients with ectopia lentis and Marfan syndrome, and in some cases, inheritance has been described as likely de novo (Körkkö J et al. J Med Genet. 2002;39:34-41; Katzke S et al. Hum Mutat. 2002;20:197-208). Additionally, this alteration has been observed to co-segregate in multiple relatives in families with bilateral ectopia lentis (Yu R et al. Am J Ophthalmol. 2006;141(6):1136-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000035129	SCV000781317	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697256	SCV000825856	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-19	criteria provided, single submitter	clinical testing	This variant is also known as R114C. This missense change has been observed in individual(s) with ectopia lentis (PMID: 11826022, 12203992, 16765689, 22950452, 25053872, 25944730, 27611364). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 62 of the FBN1 protein (p.Arg62Cys). ClinVar contains an entry for this variant (Variation ID: 42295). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function.
CeGaT Center for Human Genetics Tuebingen	RCV000493952	SCV001246574	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000493952	SCV001473223	pathogenic	not provided	2019-12-20	criteria provided, single submitter	clinical testing	The FBN1 c.184C>T; p.Arg62Cys variant (rs25403), is reported in the literature in multiple individuals with symptoms or a diagnosis of Marfan syndrome or a related aortopathy (Katzke 2002, Korkko 2002, Stheneur 2009, Yang 2009, Zhao 2013). In one family with isolated ectopia lentis, the p.Arg62Cys variant was found to segregate in all affected individuals (Zhao 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a cysteine residue in one of the calcium binding EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain normally contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; disruption of the normal pattern of 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). Based on available information, this variant is considered to be pathogenic. References: Katzke S et al. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002 Sep;20(3):197-208. Korkko J et al. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002 Jan;39(1):34-41. Loeys et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010 47(7): 476-85. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Yang H et al. Genetic testing of 248 Chinese aortopathy patients using a panel assay. Sci Rep. 2016 Sep 9;6:33002. Zhao JH et al. Ophthalmic findings in a family with early-onset isolated ectopia lentis and the p.Arg62Cys mutation of the fibrillin-1 gene (FBN1). Ophthalmic Genet. 2013 Mar-Jun;34(1-2):21-6.
Fulgent Genetics, Fulgent Genetics	RCV002482953	SCV002783525	pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114211	SCV003800653	pathogenic	Familial ectopia lentis	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.184C>T (p.Arg62Cys) results in a non-conservative amino acid change located in the fibrillin unique N-terminal (FUN) domain (IPR040872) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249372 control chromosomes (gnomAD). The variant, c.184C>T, has been reported in the literature in several individuals, who were mostly affected with Familial Ectopia Lentis, but individuals affected with (suspected) Marfan Syndrome were also described (e.g. Korkko_2002, Katzke_2002, Robinson_2011, Yu_2006, Zhao_2012, Chen_2022); in several families the variant co-segregated with ectopia lentis. These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant might affect TGF-beta1 signaling (Chaudhry_2007). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000493952	SCV004235789	pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000035129	SCV000786806	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing