Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181452 | SCV000233754 | uncertain significance | not provided | 2024-09-25 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12938084) |
| Labcorp Genetics |
RCV001313642 | SCV001504143 | uncertain significance | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-06-19 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 709 of the FBN1 protein (p.Ala709Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199988). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. 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. |
| Ambry Genetics | RCV002415770 | SCV002728975 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-05-11 | criteria provided, single submitter | clinical testing | The p.A709G variant (also known as c.2126C>G), located in coding exon 17 of the FBN1 gene, results from a C to G substitution at nucleotide position 2126. The alanine at codon 709 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV002415770 | SCV004357452 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-02-14 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with glycine at codon 709 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |