Submissions for variant NM_000138.5(FBN1):c.5540G>A (p.Cys1847Tyr)

dbSNP: rs1555396185

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589454	SCV000695562	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2019-10-08	criteria provided, single submitter	clinical testing	FBN1 c.5540G>A (p.Cys1847Tyr) is a non-conservative amino acid change in the EGF-like calcium-binding domain. Five in-silico tools predict a damaging effect. Absent in 251258 controls. No occurrence in affected individuals and no experimental evidence reported. Other missense changes p.Cys1847Arg (c.5539T>C) (PMID 16835936), p.Cys1847Trp (c.5541C>G) (PMID 17657824 and UMD). p.Cys1847Phe (c.5540G>T) (PMID 27611364) reported in patients with Marfan syndrome, suggesting a mutational hotspot. De-novo mutations affecting or creating cysteine residues in EGF consensus sequence among the criteria for a causal FBN1 mutation in revised Ghent criteria (Loeys, BL et al, 2010). A different nucleotide change c.5540G>C (p.Cys1847Ser) identified as an assumed de-novo case (both parents tested negative for c.5540G>C) at our laboratory in a patient reportedly fulfilling the Ghent criteria. Based on the evidence outlined above, c.5540G>A was re-classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767328	SCV004590986	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-03-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1847 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 16835936, 17657824, 31098894, 33483584), which suggests that this may be a clinically significant amino acid residue. 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). 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: 495623). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. 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 1847 of the FBN1 protein (p.Cys1847Tyr).