Submissions for variant NM_000138.5(FBN1):c.266G>A (p.Cys89Tyr)

dbSNP: rs112660651

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181643	SCV000233946	pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with Marfan syndrome or suspected Marfan syndrome (Tjeldhorn et al., 2006; Rand-Hendriksen et al., 2007; Stheneur et al., 2009; Proost et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a cysteine residue within an 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 EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 19293843, 17663468, 19720936, 24941995, 25907466, 11700157, 24035709, 31825148, 31730815, 17253931)
Invitae	RCV000539344	SCV000627862	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-07-11	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 200141). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 12938084, 17253931, 19293843, 19720936). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 89 of the FBN1 protein (p.Cys89Tyr).
Ambry Genetics	RCV002314686	SCV000738839	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-09-13	criteria provided, single submitter	clinical testing	The p.C89Y pathogenic mutation (also known as c.266G>A), located in coding exon 3 of the FBN1 gene, results from a G to A substitution at nucleotide position 266. The cysteine at codon 89 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-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). Internal structural analysis has suggested that this alteration eliminates a structurally important disulfide motif within a cbEGF domain involved in oligomerization of FBN1. This alteration has been detected in several individuals diagnosed with Marfan syndrome (MFS) (Pilop C et al. Circulation. 2009;120(11):983-91). In one study, this alteration was described to occur likely de novo in an individual with classic MFS (Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). Based on the supporting evidence, p.C89Y is interpreted as a disease-causing mutation.
Centre of Medical Genetics, University of Antwerp	RCV000663567	SCV002025571	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000663567	SCV004013921	pathogenic	Marfan syndrome	2023-05-04	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP3, PP5
Center for Medical Genetics Ghent, University of Ghent	RCV000663567	SCV000786878	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing