Submissions for variant NM_000138.5(FBN1):c.911G>A (p.Cys304Tyr)

dbSNP: rs1555401011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV004776291	SCV005387644	likely pathogenic	Marfan syndrome	2024-08-22	reviewed by expert panel	curation	NM_000138.5(FBN1):c. 911G>A is a missense variant in FBN1 predicted to cause a substitution of cysteine by tyrosine at amino acid 304 (p.Cys304Tyr). This variant was found in a proband with classical MFS with clinical Thoracic Aortic Dissection, Ectopia Lentis and a SS=7pt (Internal data Tokyo; PP4). This variant has been reported 1 time in ClinVar as Likely pathogenic and 1 time as uncertain significance (Variation ID: 632813). This variant is not present in gnomAD (PM2_Sup; https://gnomad.broadinstitute.org/ v4.1.0). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). The constraint z-score for missense variants affecting FBN1 is 8.2 (gnomAD v.4.1.0, PP2). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.986, PP3). 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, PM2_Sup, PP4, PP3, PP2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587808	SCV000695627	uncertain significance	not provided	2016-06-07	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.911G>A (p.Cys304Tyr) variant causes a missense change involving a conserved nucleotide located in the EGF-like #02 conserved region with 5/5 in silico tools predicting a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest causes the alteration of a cysteine, which the sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992). Therefore, alteration of cystein in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or clinical laboratories/databases. Therefore, due to the nature of this variant affecting a cysteine which is critical for protein function, the variant of interest is classified as a "VUS-possibly pathogenic," until additional information becomes available.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769657	SCV000901062	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000587808	SCV001871236	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Reported in ClinVar (ClinVar Variant ID# 495662; Landrum et al., 2016)