Submissions for variant NM_000138.5(FBN1):c.401G>A (p.Cys134Tyr)

dbSNP: rs1555405043

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588574	SCV000695530	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-04-20	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "deleterious" outcome, although these predictions have yet to be functionally assessed. The variant of interest is located in the cbEGF-like domain and causes the alteration of a cysteine to a tyrosine. "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 cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in an affected individual via a publication that shown a strong family history of MFS, although additional family members were not indicated to have been genetically tested. The variant of interest has not been reported by reputable clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Likely Pathogenic.
Invitae	RCV000692837	SCV000820681	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys134 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 16835936, 23684891), 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: 495602). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 25101912). 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 134 of the FBN1 protein (p.Cys134Tyr).
CeGaT Center for Human Genetics Tuebingen	RCV001090827	SCV001246573	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001090827	SCV003761824	pathogenic	not provided	2023-01-24	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 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: 25652356, 25101912, 17627385)
Center for Medical Genetics Ghent, University of Ghent	RCV000663684	SCV000787015	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing