Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000444024 | SCV000536660 | uncertain significance | not provided | 2018-09-10 | criteria provided, single submitter | clinical testing | The G2636S variant of uncertain significance in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified in one other individual referred for connective tissue disorder testing at GeneDx, yet observation in this individual, for whom clinical and segregation data are lacking, is not sufficient to determine the absolute pathogenicity of this variant. G2636S is not observed in large population cohorts (Lek et al., 2016). The G2636S 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, while this variant resides within the calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue. 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). |
| Labcorp Genetics |
RCV002522727 | SCV003265823 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-04-07 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2636 of the FBN1 protein (p.Gly2636Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 393275). 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 with a positive predictive value of 95%. 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. |
| All of Us Research Program, |
RCV000490638 | SCV004821042 | uncertain significance | Marfan syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000490638 | SCV000538204 | uncertain significance | Marfan syndrome | no assertion criteria provided | clinical testing |