Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035230 | SCV000058875 | likely pathogenic | Marfan syndrome | 2016-07-14 | criteria provided, single submitter | clinical testing | The p.Gly1863Glu variant in FBN1 has been identified in 2 individuals with Marfa n syndrome, and segregated with disease in 7 affected relatives from 2 families (including 1 obligate carrier; Baudhuin 2015, LMM Data). This variant was absent from 2 large population databases (ExAC and ESP). However, this variant has bee n identified in 0.4% (4/1094) of chromosomes from an unspecified population, tho ugh it is possible this is a clinical cohort (dbSNP rs113086760). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, although additional studies are required to fully establis h its clinical significance, the p.Gly1863Glu variant meets criteria to be class ified as likely pathogenic for Marfan syndrome in an autosomal dominant based up on segregation studies. |
| Labcorp Genetics |
RCV001852712 | SCV002186894 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-06-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1863 of the FBN1 protein (p.Gly1863Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 25652356; Invitae). ClinVar contains an entry for this variant (Variation ID: 42388). 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%. For these reasons, this variant has been classified as Pathogenic. |