Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004822155 | SCV005585737 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-11-18 | criteria provided, single submitter | clinical testing | The p.C2061R variant (also known as c.6181T>C), located in coding exon 50 of the FBN1 gene, results from a T to C substitution at nucleotide position 6181. The cysteine at codon 2061 is replaced by arginine, an amino acid with highly dissimilar properties. 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 TB6 domain (Ambry internal data). This variant was reported in individuals with features consistent with Marfan syndrome (Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57; 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. |
| Labcorp Genetics |
RCV005223099 | SCV005863331 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-12-15 | 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 2061 of the FBN1 protein (p.Cys2061Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 19293843). ClinVar contains an entry for this variant (Variation ID: 549333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. |
| Center for Medical Genetics Ghent, |
RCV000663853 | SCV000787211 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |