Submissions for variant NM_000138.5(FBN1):c.6752G>A (p.Cys2251Tyr)

dbSNP: rs794728256

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181579	SCV000233882	pathogenic	not provided	2014-08-13	criteria provided, single submitter	clinical testing	p.Cys2251Tyr (TGT>TAT): c.6752 G>A in exon 56 of the FBN1 gene (NM_000138.4)While the C2251Y mutation in the FBN1 gene has not been reported to our knowledge, mutations affecting this same residue (C2251R, C2251S) have been reported in association with Marfan syndrome (Yuan et al., 1999; Rommel et al., 2002). Additionally, mutations in nearby residues (E2250G, C2258R, C2258Y) have been reported in association with Marfan syndrome, further supporting the functional importance of this residue and this region of the protein. Cys2251 resides at a position that is conserved across species. In silico analysis predicts C2251Y is damaging to the protein structure/function. Furthermore, C2251Y was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, C2251Y in the FBN1 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378652	SCV001576268	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-09-24	criteria provided, single submitter	clinical testing	This variant disrupts the p.Cys2251 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 12402346, Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200093). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 2251 of the FBN1 protein (p.Cys2251Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.