Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000659526 | SCV005387636 | pathogenic | Marfan syndrome | 2024-08-22 | reviewed by expert panel | curation | NM_000138.5 c.3476G>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1159 (p.Cys1159Tyr). This variant was found in a 2-year-old proband with thoracic aortic aneurysm (TAA), ectopia lentis, and a systemic score ≥ 7, which is a highly specific phenotype for Marfan syndrome (MFS) (PP4; UZG internal data). This variant has been reported 3 times in ClinVar as pathogenic (2) and of uncertain significance (1) (Variation ID: 547309). This variant has been identified in 4 other individuals meeting the revised Ghent criteria for a clinical diagnosis of MFS, as de novo in a neonate with severe TAA and a systemic score of 6, and in 2 additional individuals who did not meet diagnostic criteria either but have phenotypes strongly suggestive of MFS (PS4, PM6_supporting; PMIDs: 35831148, 31523900, 34628919; UZG, Mayo, & Invitae internal data). It is not present in gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3; REVEL = 0.981). The constraint z-score for missense variants affecting FBN1 is 8.2 (PP2; gnomAD v4.1.0). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1_strong, PP2, PP3, PP4, PM2_supporting, PM6_supporting. |
| Center for Human Genetics, |
RCV000659526 | SCV000781353 | uncertain significance | Marfan syndrome | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003767906 | SCV004571018 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-05-12 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1159 of the FBN1 protein (p.Cys1159Tyr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1159 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 34628919; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). 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: 547309). This missense change has been observed in individuals with Marfan syndrome (PMID: 34628919; Invitae). |
| Center for Medical Genetics Ghent, |
RCV000659526 | SCV000786970 | pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |