Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002340074 | SCV002639848 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-09-30 | criteria provided, single submitter | clinical testing | The p.C1513G variant (also known as c.4537T>G), located in coding exon 36 of the FBN1 gene, results from a T to G substitution at nucleotide position 4537. The cysteine at codon 1513 is replaced by glycine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #22 domain. 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). This particular alteration has been reported in one individual with classical Marfan syndrome (MFS) who was heterozygous for a second, nearby FBN1 variant (c.4536C>A p.D1512E) (Yoo EH et al. Clin. Genet. 2010;77:177-82). Two likely pathogenic alterations in the same codon (p.C1513R and p.C1513W) have also been associated with MFS (Kainulainen K et al. Nat. Genet. 1994;6:64-9; Ganesh A et al. Arch. Ophthalmol. 2006;124:205-9). Internal structural analysis indicates that this alteration disrupts a disulfide bond and is structurally destabilizing (Lee SS et al. Structure. 2004;12(4):717-29). 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 |
RCV003775914 | SCV004592927 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-01-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1513 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 8136837, 16476890), 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: 1741306). 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 glycine, which is neutral and non-polar, at codon 1513 of the FBN1 protein (p.Cys1513Gly). |