Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035178 | SCV000058820 | pathogenic | Marfan syndrome | 2011-06-03 | criteria provided, single submitter | clinical testing | The Cys123Tyr variant has been reported in 3 individuals with a clinical diagnos is of or suspected Marfan syndrome and was absent from 220 control chromosomes ( Arbustini 2005, D'Amore 2005, Attanasio 2008). In addition, this variant affects a cysteine residue. Cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999). The Cys123Tyr variant also lies within a functional domain of FBN1 and is likely to be responsible for the clinical featu res observed in this individual. Therefore, this variant is highly likely to be pathogenic. |
| Invitae | RCV002514148 | SCV003442992 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-05-05 | 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 123 of the FBN1 protein (p.Cys123Tyr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 42340). This missense change has been observed in individuals with FBN1-related conditions (PMID: 16222657, 18435798, 21932315). |
| Center for Genomics, |
RCV003224116 | SCV003919953 | pathogenic | Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome | 2022-12-29 | criteria provided, single submitter | clinical testing | This variant has been reported in the literature in at least 4 individuals with clinical suspicion or diagnoses of Marfan syndrome, with ectopia lentis noted in each patient (D'Amore 2005 PMID: 15983637; Arbustini 2005 PMID: 16222657; Attanasio 2008 PMID: 18435798; Zadeh 2011 PMID: 21932315). This variant is absent from gnomAD. It is present in ClinVar, with the only submitting laboratory classifying it as pathogenic (Variation ID: 42340). This variant alters a cysteine residue in an EGF-like domain of the encoded protein; cysteine residues in EGF-like and cbEGF-like domains of the fibrillin-1 protein are well-established as important for protein structure and function (Robinson 2006 PMID: 16571647; Faivre 2007 PMID: 17701892). Evolutionary conservation and computational prediction tools strongly support that this variant impacts the protein. Other variants at this same amino acid position (p.Cys123Arg, p.Cys123Gly) have also been reported in association with disease (Zhou 2021 PMID: 33576469; Li 2019 PMID: 31098894), further supporting the functional importance of the wild-type residue. In summary, this variant is classified as pathogenic. |