Submissions for variant NM_000138.5(FBN1):c.1453C>T (p.Arg485Cys)

dbSNP: rs137854485

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663457	SCV004123038	pathogenic	Marfan syndrome	2023-11-16	reviewed by expert panel	curation	NM_00138 c.1453C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 485 (p.Arg484Cys). This variant has been identified in the literature in at least seven probands with features consistent with or suggestive of Marfan syndrome including thoracic aortic aneurysm and dissection (TAAD) with or without additional features (PS4; PMIDs: 16342915, 19293843, 24793577, 30485715). It was found in the homozygous state in two cousins with bilateral ectopia lentis (EL) and additional features of Marfan syndrome; of note, in both instances the variant was inherited from mildly affected or apparently unaffected heterozygous parents (PMID: 17568394). It was identified in trans with a different FBN1 pathogenic variant in three siblings with isolated EL (Bichat internal data); clinical information for the heterozygous parents was not available. The variant has also been identified in the heterozygous state in 5 additional internal probands diagnosed with TAAD with or without systemic features (UZG, Johns Hopkins University, Bichat, & University of Tokyo internal data). It has been found to segregate in the heterozygous state with features of Marfan syndrome in at least 19 individuals among five different families (PP1_strong; PMID: 30485715; Johns Hopkins & Bichat internal data). It has been identified as de novo once with confirmed maternity/paternity in an internal proband with a non-specific phenotype (PS2_supporting; PMID: 19293843; UZG internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis are unclear about the variant’s predicted impact on the protein’s structure or function. The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PP1_strong, PM1, PS2_supporting, PM2_supporting, PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150705	SCV000198107	uncertain significance	not specified	2018-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000809693	SCV000949859	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 485 of the FBN1 protein (p.Arg485Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 16342915, 17568394, 19839986, 24793577, 30485715, 30739908). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16466). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390114	SCV002701891	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-01-29	criteria provided, single submitter	clinical testing	The p.R485C pathogenic mutation (also known as c.1453C>T), located in coding exon 11 of the FBN1 gene, results from a C to T substitution at nucleotide position 1453. The arginine at codon 485 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #4 domain. This mutation has been reported in multiple individuals with Marfan syndrome (MFS) and Marfan-like findings, including one reported de novo MFS case (Baumgartner C et al. Methods Inf Med, 2005;44:487-97; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). Cosegregation in affected family members has been reported in two families with thoracic aortic aneurysms, abdominal aortic aneurysms, and other clinical findings consistent with MFS (Overwater E et al. Mol Genet Genomic Med, 2018 Nov;[Epub ahead of print]). In a consanguineous family, this mutation was detected as homozygous in two cousins with MFS, while their heterozygous parents were described as not having symptoms of MFS (de Vries BB et al. Eur. J. Hum. Genet., 2007 Sep;15:930-5). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV002390114	SCV004240560	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-12-28	criteria provided, single submitter	clinical testing
OMIM	RCV000017930	SCV000038209	pathogenic	Marfan syndrome, autosomal recessive	2007-09-01	no assertion criteria provided	literature only
Center for Medical Genetics Ghent, University of Ghent	RCV000663457	SCV000786750	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing