Submissions for variant NM_000138.5(FBN1):c.7787A>G (p.Tyr2596Cys)

dbSNP: rs1566891404

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756135	SCV000883856	likely pathogenic	not provided	2017-06-09	criteria provided, single submitter	clinical testing	The FBN1 c.7787A>G;p.Tyr2596Cys variant has been published in at least one individual that met diagnostic criteria for Marfan syndrome (Proost 2015). Additionally, our laboratory has detected this variant in an individual with a clinical diagnosis of Marfan syndrome. The variant has not been described in the ClinVar database, the dbSNP variant database, or in the general population-based databases. The amino acid at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Additionally, this variant occurs in one of the EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; creation of a novel cysteine may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists creation of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Considering available information, this variant is classified as likely pathogenic. References: Loeys et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010 47(7): 476-85. Proost D et al. Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. Hum Mutat. 2015 Aug;36(8):808-14. Wu et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem. Biol. 1995 2(2):91-7.
Centre of Medical Genetics, University of Antwerp	RCV002246008	SCV002025460	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS5, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855870	SCV002266145	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2596 of the FBN1 protein (p.Tyr2596Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome and/or thoracic aortic aneurysm and dissection (PMID: 25907466; Invitae). ClinVar contains an entry for this variant (Variation ID: 618118). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000756135	SCV003931073	likely pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Introduces a new cysteine residue within a calcium-binding 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 calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); 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: 10486319, 25907466)