Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002313276 | SCV000738923 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-09-20 | criteria provided, single submitter | clinical testing | The p.C1984Y variant (also known as c.5951G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 5951. The cysteine at codon 1984 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #30 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Two alterations affecting the same cysteine, C1984R and C1984G, have been reported in individuals with Marfan syndrome (Baetens M et al. Hum. Mutat., 2011 Sep;32:1053-62; Franken R et al. Eur. Heart J., 2016 Nov;37:3285-3290). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265820 | SCV002547852 | likely pathogenic | Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections | 2022-05-23 | criteria provided, single submitter | clinical testing | Variant summary: FBN1 c.5951G>A (p.Cys1984Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251092 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5951G>A has been reported in at least one individual affected with Marfan Syndrome (UMD-FBN1 database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however, the sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two-thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage (Dietz_1992). Therefore, the substitution of a cysteine may disrupt the structure of the FBN1 protein, affecting its function. Two other variants affecting cysteine1984 residue have been classified as pathogenic within ClinVar or reported in HGMD database (c.5950T>C/p.Cys1984Arg, c.5950T>G/p.Cys1984Gly). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV003767803 | SCV004570960 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-12-30 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 519792). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1984Arg amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16571647, 16905551, 17701892, 19349279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 missense change has been observed in individuals with Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1984 of the FBN1 protein (p.Cys1984Tyr). |
| Center for Medical Genetics Ghent, |
RCV000663838 | SCV000787195 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |