Submissions for variant NM_000138.5(FBN1):c.2627G>A (p.Cys876Tyr)

dbSNP: rs794728193

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181463	SCV000233765	likely pathogenic	not provided	2017-05-24	criteria provided, single submitter	clinical testing	p.Cys876Tyr (TGC>TAC): c.2627 G>A in exon 22 of the FBN1 gene (NM_000138.4)The Cys876Tyr variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Cys876Tyr variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The Cys876 residue is conserved across species. In silico analysis predicts Cys876Tyr is damaging to the protein structure/function. Mutations in nearby residues (Cys875Arg, Gly880Ser, Ala882Val) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Cys876Tyr variant was not observed in approximately 6500 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, while Cys876Tyr is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001231222	SCV001403735	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2019-08-08	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Cys876 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 26787436, 28855619), which suggests that this may be a clinically significant amino acid residue. 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 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 sequence change replaces cysteine with tyrosine at codon 876 of the FBN1 protein (p.Cys876Tyr). 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 an individual affected with Marfan syndrome (PMID: 26787436). ClinVar contains an entry for this variant (Variation ID: 199999).
Center for Medical Genetics Ghent, University of Ghent	RCV000663560	SCV000786871	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing