Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000505745 | SCV000234010 | uncertain significance | not provided | 2018-11-01 | criteria provided, single submitter | clinical testing | A variant of uncertain significance was identified in the FBN1 gene. It has not been published as a pathogenic variant,nor has it been reported as a benign variant to our knowledge. The L2626Q variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The L2626Q variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and insilico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants innearby residues (N2624S, N2624T, N2624K, G2627R, Y2629C) have been reported in the Human Gene MutationDatabase in association with Marfan syndrome (Stenson et al., 2014). Nevertheless, the L2626Q variant does notaffect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in thecalcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfansyndrome (Collod-Beroud et al., 2003). |
| Labcorp Genetics |
RCV000690617 | SCV000818314 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-05-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2626 of the FBN1 protein (p.Leu2626Gln). 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. 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: 200200). This missense change has been observed in individuals with Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). |