Submissions for variant NM_000138.5(FBN1):c.6032G>A (p.Cys2011Tyr)

dbSNP: rs886038967

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003888667	SCV004704626	likely pathogenic	Marfan syndrome	2024-02-22	reviewed by expert panel	curation	The NM_00138 c.6032G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 2011 (p.Cys2011Tyr). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 263898). At least two probands with clinical features of Marfan syndrome carry the same variant (internal lab data, PS4_Sup). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/v2.1.1). This variant affects a cysteine residue in a calcium binding EGF-like domain. Cysteine residues in these domains are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Other missense variants disrupting the Cysteine at this position, (i.e. p.Cys2011Arg and p.Cys2011Ser), have been reported in individuals with features of Marfan syndrome (PMID 29907982, 31163209). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.921, 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_Strong, PS4_Sup, PM2_Sup, PP2, PP3
Ambry Genetics	RCV002310892	SCV000319401	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2015-03-19	criteria provided, single submitter	clinical testing	The p.C2011Y variant (also known as c.6032G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6032. The cysteine at codon 2011 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Internal structural analysis indicates that this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #30 (Ambry internal data). A likely pathogenic alteration, p.C2011R, has been described in the same codon (Overwater E et al. Hum. Mutat., 2018 Sep;39:1173-1192). 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.
GeneDx	RCV000413845	SCV000490525	likely pathogenic	not provided	2019-03-28	criteria provided, single submitter	clinical testing	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).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260318	SCV001437243	uncertain significance	not specified	2020-09-16	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6032G>A (p.Cys2011Tyr) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) 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 251146 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6032G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, missense mutations affecting or creating cysteine residues or located within the conserved resides of the EGF consensus sequence are listed among the criteria for a causal FBN1 mutation when identified as de-novo (with proven paternity) in the revised Ghent criteria for the diagnosis of Marfan and related conditions (Loeys, BL et al, 2010). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV002518701	SCV003353074	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-05-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Marfan syndrome (external communication). ClinVar contains an entry for this variant (Variation ID: 263898). 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. 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 disrupts the p.Cys2011 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29907982, 31163209; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. 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 2011 of the FBN1 protein (p.Cys2011Tyr).