Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000150698 | SCV000198069 | likely pathogenic | Marfan syndrome | 2018-03-15 | criteria provided, single submitter | clinical testing | The p.Cys2170Tyr variant in FBN1 has been identified as a de novo occurrence in 1 individual with a clinical diagnosis of Marfan syndrome (LMM data) and was abs ent from large population studies. This variant affects a cysteine residue; cyst eine substitutions are a common finding in individuals with Marfan syndrome (Sch rijver, 1999). Two other variants involving this residue, p.Cys2170Phe and p.Cys 2170Ser, have been associated with Marfan syndrome (Ng 2002, Tjeldhorn 2006), su ggesting that changes at this position are not tolerated. Computational predict ion tools and conservation analysis suggest that the p.Cys2170Tyr variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Cys2170Tyr variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PM6; PP3; PP4. |
| Labcorp Genetics |
RCV002514897 | SCV003320694 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-02-20 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 163467). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2170 of the FBN1 protein (p.Cys2170Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). 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. 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). This variant disrupts the p.Cys2170 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17253931, 27906200), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |