Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004586027 | SCV000052364 | uncertain significance | not specified | 2024-04-02 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.2479T>C (p.Ser827Pro) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2479T>C has been reported in the literature in individuals affected with clinical features of Marfan Syndrome (e.g. Groth_2017). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27906200). ClinVar contains an entry for this variant (Variation ID: 36051). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV002513247 | SCV003442972 | uncertain significance | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 827 of the FBN1 protein (p.Ser827Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 27906200). ClinVar contains an entry for this variant (Variation ID: 36051). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV004589523 | SCV005079049 | uncertain significance | not provided | 2023-11-16 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign in association with an FBN1-related disorder to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27906200, 12938084) |