Submissions for variant NM_000138.5(FBN1):c.199T>C (p.Cys67Arg)

dbSNP: rs2140737496

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003476886	SCV004218522	likely pathogenic	Marfan syndrome	2023-12-21	reviewed by expert panel	curation	The NM_00138 c.199T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 67 (p.Cys67Arg). This variant was found in a proband with thoracic aortic aneurysm and ectopia lentis which is a highly specific phenotype for Marfan syndrome (Internal data, PP4). This variant has been reported 1 in ClinVar as likely pathogenic and 1 time as uncertain significance (Variantion ID: 1380036). Three other probands with clinical features of Marfan syndrome carry the same variant (PMID 19839986, 33436942, 34281902, PS4_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in the fibrillin unique N-terminal (FUN) domain. A different missense variant impacting the same residue, p.Cys67Ser, has previously been established as likely pathogenic, and reported in individuals with clinical features of Marfan syndrome (PMID 27906200, internal data, PM5). Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.883, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM5, PM2_Sup, PP2, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001917113	SCV002152176	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 67 of the FBN1 protein (p.Cys67Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FBN1-related conditions (PMID: 19839986, 33436942). ClinVar contains an entry for this variant (Variation ID: 1380036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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). This variant disrupts the p.Cys67 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 27906200), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002422956	SCV002717721	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-06-08	criteria provided, single submitter	clinical testing	The p.C67R variant (also known as c.199T>C), located in coding exon 2 of the FBN1 gene, results from a T to C substitution at nucleotide position 199. The cysteine at codon 67 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the FUN domain. This alteration has been reported in one subject in a Marfan syndrome cohort (Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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). However, since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. Family studies may help to elucidate the clinical impact of this alteration.