Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523557 | SCV000620601 | uncertain significance | not provided | 2017-09-05 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the FBN1 gene. The K278E variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to lysine (K) are tolerated across species, and K278E 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. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, while K278E is located within a calcium-binding EGF-like domain of the FBN1 gene, this variant 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). |
| Labcorp Genetics |
RCV001066350 | SCV001231357 | likely benign | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-11-14 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004003632 | SCV004820625 | uncertain significance | Marfan syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 278 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 FBN1-related disorders in the literature. This variant has been identified in 9/282840 chromosomes 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. |