Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587806 | SCV000695484 | pathogenic | Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections | 2016-06-01 | criteria provided, single submitter | clinical testing | Variant summary: The FBN1 c.2261A>G (p.Tyr754Cys) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant affects a conserved tyrosine that is involved in the interaction between adjacent EGF domains. It also introduces a seventh cysteine into exon 18 and is predicted to have a major effect on the structure of the protein. These predictions were confirmed by immunohistochemical staining of fibrillin in fibroblast culture from affected carriers which showed limited amount of fibrillin in the extracellular matrix in addition to disorganized and clumped appearance rather than fibrous structure. This variant is absent from 121586 control chromosomes. This variant has been reported in multiple affected families with MFS and FEL and was shown to co-segregate with disease. Taken together, the variant was classified as "Pathogenic". |
| Invitae | RCV003764585 | SCV004571022 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-08-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 754 of the FBN1 protein (p.Tyr754Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectopia lentis and/or Marfan syndrome (PMID: 15032979, 22393277, 31950671). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16460). 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. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000017923 | SCV000038202 | pathogenic | Marfan syndrome | 2004-01-01 | no assertion criteria provided | literature only | |
| Center for Medical Genetics Ghent, |
RCV000017923 | SCV000786833 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |