Submissions for variant NM_000138.5(FBN1):c.2495G>A (p.Cys832Tyr)

dbSNP: rs397515775

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035145	SCV000058786	likely pathogenic	Marfan syndrome	2008-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000427032	SCV000516936	pathogenic	not provided	2022-05-19	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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10464652, 19839986, 31447099, 12938084, 10486319, 16222657, 17657824, 31098894, 24199744, 29357934)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000035145	SCV000839956	pathogenic	Marfan syndrome	2018-04-03	criteria provided, single submitter	clinical testing	This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene has been reported in multiple unrelated individuals with Marfan syndrome (PMID: 10464652, 16222657, 17657824) and is extremely rare in the general population. Other reports have also observed different changes at the same amino acid in patients with Marfan syndrome (PMID: 19839986, 24793577). There is also strong functional data supporting pathogenesis (PMID: 10486319, 10464652). This c.2495G>A (p.Cys832Tyr) variant in the FBN1 gene is classified as pathogenic.
Invitae	RCV001215995	SCV001387766	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys832 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19839986, 27906200), which suggests that this may be a clinically significant amino acid residue. 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). 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. ClinVar contains an entry for this variant (Variation ID: 42311). This missense change has been observed in individuals with Marfan syndrome (PMID: 10464652, 16222657, 17657824, 24199744, 29357934). It has also been observed to segregate with disease in related individuals. 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 832 of the FBN1 protein (p.Cys832Tyr).