Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002313267 | SCV000738907 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-06-15 | criteria provided, single submitter | clinical testing | The p.C2251S variant (also known as c.6751T>A), located in coding exon 55 of the FBN1 gene, results from a T to A substitution at nucleotide position 6751. The cysteine at codon 2251 is replaced by serine, an amino acid with dissimilar properties, and is located in the cbEGF-like #35 domain. This alteration has been reported in a cohort of subjects with Marfan syndrome and related disorders (Yuan B. et al. Hum. Mutat. 1999;14(5):440-6). In addition, another alteration affecting the same amino acid, p.C2251R (c.6751T>C), has been reported in association with Marfan syndrome (Rommel K. et al. Hum. Mutat. 2002 Nov;20(5):406-7). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cbEGF domain #35 (Downing AK. et al. Cell. 1996 May:17;85(4):597-605). 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 |
RCV001238290 | SCV001411093 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-09-20 | 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). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2251 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 12402346, Invitae), which suggests that this may be a clinically significant amino acid residue. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals with clinical features of Marfan syndrome (PMID: 10533071). ClinVar contains an entry for this variant (Variation ID: 519780). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 2251 of the FBN1 protein (p.Cys2251Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. |