Submissions for variant NM_000138.5(FBN1):c.2243G>A (p.Cys748Tyr)

dbSNP: rs1064794282

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486760	SCV000568641	likely pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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 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); This variant is associated with the following publications: (PMID: 26770496, 28391405, 30675029, 19328768, 12203992, 12161601, 12938084, 31830381, 37203318, 19839986)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588016	SCV000695481	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2243G>A (p.Cys748Tyr) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes. c.2243G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g. Katzke_2002, Hung_2009, Xu_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, this variant disrupts one of the cysteine residues in the EGF-like domain, which are known to play an important role in protein structure and interactions with other molecules, suggesting that the variant could affect protein function (e.g. Dietz_1992). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000696385	SCV000824945	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2018-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 748 of the FBN1 protein (p.Cys748Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Marfan syndrome (PMID: 12203992, 19839986, 12161601, 26770496). ClinVar contains an entry for this variant (Variation ID: 420086). The observation of one or more missense substitutions at this codon (p.Cys748Tyr and p.Cys748Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 19839986, 29357934). For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains 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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000486760	SCV002103259	pathogenic	not provided	2021-04-09	criteria provided, single submitter	clinical testing	PS4_moderate, PM1, PM5, PP3, PP4, PM2_supporting
Arcensus	RCV002466256	SCV002564609	pathogenic	Marfan syndrome	2013-02-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002466256	SCV004047179	pathogenic	Marfan syndrome		criteria provided, single submitter	clinical testing	The FBN1 c.2243G>A variant has been reported in individuals affected with Marfan syndrome (Katzke et. al., 2002; Hung et. al., 2009) and one or more missense substitutions at this codon (p.Cys748Tyr and p.Cys748Arg) in affected individuals suggests that this may be a clinically significant residue (Hung CC et. al., 2009; Becerra-Muñoz VM et. al., 2018). This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (Mellody et. al., 2006; Ono RN et. al., 2009). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (Robinson PN et. al., 2006; Katzke et. al., 2002). The p.Cys748Tyr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database (Pathogenic/Likely Pathogenic). The amino acid Cys at position 748 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys748Tyr in FBN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.