Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000989337 | SCV001139625 | likely pathogenic | Marfan syndrome | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003769304 | SCV004570997 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 166 of the FBN1 protein (p.Cys166Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 28941062, 32679894). ClinVar contains an entry for this variant (Variation ID: 803098). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004030115 | SCV005032591 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-10-06 | criteria provided, single submitter | clinical testing | The p.C166R variant (also known as c.496T>C), located in coding exon 5 of the FBN1 gene, results from a T to C substitution at nucleotide position 496. The cysteine at codon 166 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been detected in individuals from cohorts with clinically diagnosed or suspected Marfan syndrome (Vatti L et al. Am J Med Genet A, 2017 Nov;173:2995-3002; Stark VC et al. Genes (Basel), 2020 Jul;11). 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 this alteration eliminates a disulfide bond critical for the structural integrity of the EGF3 domain (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |