Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522194 | SCV000618130 | likely pathogenic | not provided | 2017-04-20 | criteria provided, single submitter | clinical testing | Although the G2627E likely pathogenic variant in the FBN1 gene has not been published as pathogenic or benign to our knowledge, it has been identified in one individual with a clinical diagnosis of Marfan syndrome referred for genetic testing at GeneDx. In addition, G2627E is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G2627E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis also predicts G2627E is probably damaging to the protein structure/function. This substitution occurs within a calcium-binding EGF-like domain of the FBN1 gene at a position that is conserved across species and in all calcium-binding EGF-like domains in the FBN1 gene. Moreover, this residue is involved in domain-domain packing between two calcium-binding EGF-like domains (Downing et al., 1996; Stenson et al., 2014). Furthermore, a missense variant in the same residue (G2627R) has been reported in association with Marfan syndrome (Karttunen et al., 1994). Nevertheless, cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003), and the functional impact of a glycine to glutamic acid substitution at this position requires further study. In summary, G2627E in the FBN1 gene is interpreted as a likely pathogenic variant |
| Ambry Genetics | RCV002413405 | SCV002681002 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2021-03-02 | criteria provided, single submitter | clinical testing | The p.G2627E variant (also known as c.7880G>A), located in coding exon 63 of the FBN1 gene, results from a G to A substitution at nucleotide position 7880. The glycine at codon 2627 is replaced by glutamic acid, an amino acid with similar properties, and is located in the cbEGF-like #42 domain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural assessment, this alteration disrupts the formation of the calcium-binding in cbEGF domain #42 of FBN1, and it’s interaction with cbEGF domain #41 (Lee SS et al. Structure, 2004 Apr;12:717-29; Jensen SA et al. Structure, 2009 May;17:759-68). In addition, another alteration affecting the same amino acid, p.G2627R (c.7879G>A and c.7879G>C), has been reported in association with Marfan syndrome (Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67). 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 |
RCV003766945 | SCV004596935 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-07-25 | criteria provided, single submitter | clinical testing | 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 variant disrupts the p.Gly2627 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7977366, 19839986). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 449756). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2627 of the FBN1 protein (p.Gly2627Glu). |