Submissions for variant NM_000138.5(FBN1):c.2624G>A (p.Cys875Tyr)

dbSNP: rs886039038

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003476879	SCV004218526	likely pathogenic	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	The NM_00138 c.2624G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 875 (p.Cys875Tyr). This variant has been reported three times in ClinVar: twice as likely pathogenic and once as uncertain significance (Variation ID: 264089). A different missense variant impacting the same residue, p.Cys875Arg has been previously reported in individuals with clinical features of Marfan syndrome and found to segregate with disease in multiple affected relatives from one family (PMID 19293843, 28973303, internal data; PM5). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant affects a cysteine residue in a hybrid domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.986, PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PM2_Sup, PP2, PP3.
Ambry Genetics	RCV000769646	SCV000319764	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2015-05-27	criteria provided, single submitter	clinical testing	The p.C875Y variant (also known as c.2624G>A), located in coding exon 21 of the FBN1 gene, results from a G to A substitution at nucleotide position 2624. The cysteine at codon 875 is replaced by tyrosine, an amino acid with highly dissimilar properties, in the hybrid motif #02 domain. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Jensen SA et al. Structure 2009;17(5):759-68). Another alteration at the same codon, p.C875R, has been reported in a familial case of classical Marfan syndrome (Stheneur C et al. Eur J Hum Genet. 2009;17(9):1121-8). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769646	SCV000901047	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV001063194	SCV001228030	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2019-12-11	criteria provided, single submitter	clinical testing	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). 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 disrupts the p.Cys875 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 28973303), which suggests that this may be a clinically significant amino acid residue. 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 has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 264089). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 875 of the FBN1 protein (p.Cys875Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.