Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002614 | SCV001160592 | likely pathogenic | not specified | 2019-05-16 | criteria provided, single submitter | clinical testing | The FBN1 c.503G>A; p.Cys168Tyr variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a cysteine residue in one of the calcium binding EGF-like domains of fibrillin-1 (Wu 1995). Each EGF-like domain contains six highly-conserved cysteines and the disulfide bridges formed between these residues are essential for protein folding; loss of one of these cysteines may interfere with proper disulfide bridge formation, disrupting protein structure. Accordingly, the revised Ghent nosology for Marfan syndrome lists missense variants of cysteine residues as one of the criteria for classification of a variant as pathogenic (Loeys 2010). Additionally, other amino acid substitutions at this codon (Arg, Gly, Trp) have been reported in individuals with Marfan syndrome and/or ectopia lentis, and are considered pathogenic or likely pathogenic (Jin 2007, Milla 2012, Proost 2015). Based on available information, the p.Cys168Tyr variant is considered to be likely pathogenic. References: Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007 Jul 24;13:1280-4. Loeys et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010 47(7): 476-85. Milla E et al. Novel FBN1 mutation causes Marfan syndrome with bilateral ectopia lentis and refractory glaucoma. Eur J Ophthalmol. 2012 Jul-Aug;22(4):667-9. Proost D et al. Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. Hum Mutat. 2015 Aug;36(8):808-14. Wu et al. Fibrillin domain folding and calcium binding: significance to Marfan syndrome. Chem. Biol. 1995 2(2):91-7. |
| Labcorp Genetics |
RCV001061712 | SCV001226464 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-07-19 | criteria provided, single submitter | clinical testing | 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: 812041). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). 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 168 of the FBN1 protein (p.Cys168Tyr). 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.Cys168 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17679947, 22034023, 25907466), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |