Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002036675 | SCV002317740 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-05-14 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. 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. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2070 of the FBN1 protein (p.Cys2070Tyr). |
| Ambry Genetics | RCV002352775 | SCV002655073 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-06-27 | criteria provided, single submitter | clinical testing | The p.C2070Y variant (also known as c.6209G>A), located in coding exon 50 of the FBN1 gene, results from a G to A substitution at nucleotide position 6209. The cysteine at codon 2070 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the TGFBP #06 domain. This variant has been reported in individuals with phenotypes consistent with Marfan syndrome (Ambry internal data; Invitae pers. comm.). 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive TGFBP #06 domain. 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. |