Submissions for variant NM_000138.5(FBN1):c.1463G>A (p.Cys488Tyr)

dbSNP: rs1555400372

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058787	SCV001223380	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-05-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 488 of the FBN1 protein (p.Cys488Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 549017). 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 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.Cys488 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 15241795, 18435798, 19293843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001805786	SCV002053847	likely pathogenic	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome		criteria provided, single submitter	research
Ambry Genetics	RCV002388172	SCV002697193	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-08-14	criteria provided, single submitter	clinical testing	The p.C488Y pathogenic mutation (also known as c.1463G>A), located in coding exon 11 of the FBN1 gene, results from a G to A substitution at nucleotide position 1463. The cysteine at codon 488 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #04 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive EGF/cbEGF domain #04. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, p.C488R (c.1462T>C), has been noted in a subject with features of Marfan syndrome (Attanasio M et al. Eur J Med Genet, 2013 Jul;56:356-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Medical Genetics Ghent, University of Ghent	RCV000663459	SCV000786752	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing