Submissions for variant NM_000138.5(FBN1):c.2287T>G (p.Cys763Gly)

dbSNP: rs1555399361

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663525	SCV004218525	pathogenic	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	The NM_00138 c.2287T>G is a missense variant in FBN1 predicted to cause a substitution of a cysteine by glycine at amino acid 763 (p.Cys763Gly). This variant was found in two probands with a clinical diagnosis of Marfan syndrome (internal data, PP4, PS4_Supporting). In one of these probands the variant was found de novo with assumed paternity and maternity (PM6). This variant has been reported 3 times in ClinVar, once as pathogenic, once as likely pathogenic and once as uncertain significance (Variation ID: 549070). To our knowledge, this variant has not previously been reported in individuals affected with Marfan syndrome in the literature. This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.98) (PP3). 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: PM1_Strong, PM6, PS4_Supporting, PM2_Sup, PP2, PP3, PP4.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000663525	SCV000898700	pathogenic	Marfan syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 1 individual with a clinical suspicion or diagnosis of Marfan syndrome (Stengl 2020 PMID: 33059708), and as de novo in 1 individual with bilateral ectopia lentis and aortic dilatation at an external institution (personal communication). This variant is not present in large control databases but is present in ClinVar (Variation ID: 549070). Of note, this variant is located in a cbEGF-like domain, in which cysteine residues have been shown to be critical to protein structure and stability; missense variants at cysteine residues within cbEGF-like domains are enriched in patients with Marfan syndrome (Robinson 2006 PMID: 16571647; Faivre 2007 PMID: 17701892; Dietz 2017 PMID: 20301510). Additionally, the FBN1 gene has a gnomAD missense constraint z-score of 5.06, suggesting that benign missense variation in FBN1 is uncommon (Lek 2016 PMID:27535533). Evolutionary conservation and computational predictive tools support that this variant impacts the protein. In summary, this variant is classified as pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV000663525	SCV002025531	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000663525	SCV000786834	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing