Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181699 | SCV000234002 | pathogenic | not provided | 2022-04-26 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 10425041, 12938084) |
| Invitae | RCV001060030 | SCV001224691 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-01-02 | 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 2142 of the FBN1 protein (p.Cys2142Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 10425041; Invitae). ClinVar contains an entry for this variant (Variation ID: 200192). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000663870 | SCV002557745 | pathogenic | Marfan syndrome | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is associated with autosomal dominant disease. This gene is predominantly associated with autosomal dominant disease, however some individuals have been reported with an autosomal recessive form of Marfan syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF domain (NCBI). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to a serine and an arginine have been reported as likely pathogenic (ClinVar) and in an individual with Marfan syndrome (PMID: 30087447) respectively. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as pathogenic and once as likely pathogenic in ClinVar. This variant has also been reported in an individual with classic Marfan syndrome (PMID: 10425041). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Ambry Genetics | RCV002362930 | SCV002660313 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-04-09 | criteria provided, single submitter | clinical testing | The p.C2142Y variant (also known as c.6425G>A), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6425. The cysteine at codon 2142 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with classical Marfan syndrome (El-Aleem AA et al. Hum. Mutat., 1999 Aug;14:181). 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). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive cb EGF-like domain 32. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Center for Medical Genetics Ghent, |
RCV000663870 | SCV000787230 | likely pathogenic | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |