Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002311083 | SCV000319886 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-04-29 | criteria provided, single submitter | clinical testing | The p.C377R variant (also known as c.1129T>C), located in coding exon 9 of the FBN1 gene, results from a T to C substitution at nucleotide position 1129. The cysteine at codon 377 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 TB domain 1 (Ambry internal data). This alteration has been reported in an individual with a clinical diagnosis of Marfan syndrome (Ambry internal data). 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. |
| Invitae | RCV000804876 | SCV000944814 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2018-12-20 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 264158). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 377 of the FBN1 protein (p.Cys377Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. |