Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001249769 | SCV001423803 | likely pathogenic | Marfan syndrome | 2019-10-11 | criteria provided, single submitter | clinical testing | The FBN1 c.4217A>G (p.Asp1406Gly) variant is a missense variant that has been reported in a heterozygous state in one individual with classic Marfan syndrome diagnosed according to the Berlin or revised Ghent nosology (Tiecke et al. 2001). The variant was inherited and was described as segregating with the phenotype in the family, although no details are given. This variant is not found in the Genome Aggregation Database despite its location in a region of good sequencing coverage. It is therefore presumed to be rare. The p.Asp1406Gly variant affects a conserved residue in one of the 47 calcium binding EGF repeats of fibrillin-1 and is predicted to have a deleterious effect by multiple in silico algorithms. In vitro analysis also suggest that the variant may increase the susceptibility of fibrillin-1 to protease degradation (Robinson and Booms 2001). Based on the collective evidence, the p.Asp1406Gly variant is classified as likely pathogenic for Marfan syndrome. |
| Invitae | RCV001879762 | SCV002313008 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1406 of the FBN1 protein (p.Asp1406Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 11175294, 17657824; Invitae). ClinVar contains an entry for this variant (Variation ID: 973318). 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. Experimental studies have shown that this missense change affects FBN1 function (PMID: 11706995). 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. |