Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000220364 | SCV000271224 | likely pathogenic | Marfan syndrome | 2015-02-04 | criteria provided, single submitter | clinical testing | The p.Cys100Tyr variant in FBN1 has been identified in 1 African American indivi dual with Marfan syndrome, 1 Chinese individual with Marfan syndrome, and segreg ated with disease in 1 affected relative (LMM unpublished data, Chung 2009). It was absent from large population studies. Additionally, another variant at the s ame position (p.Cys100Phe) has been identified to occur de novo in 1 Asian indiv idual with Marfan syndrome (LMM unpublished data), suggesting that a change at t his position may not be tolerated. Computational prediction tools and conservati on analysis suggest that the p.Cys100Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermor e, this variant affects a highly conserved cysteine residue in the EGF-like doma ins, which is a common finding in individuals with Marfan syndrome (Schrijver 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Cys100Tyr variant is likely pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000220364 | SCV002557757 | likely pathogenic | Marfan syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 are commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects are associated with 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 predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with 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) 0601 - Variant affects a well-established functional cysteine residue of an EGF-like domain. Cysteine substitutions in EGF-like domains are commonly disease-causing (PMID: 31227806). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to phenylalanine and arginine have been described as pathogenic or likely pathogenic in ClinVar and the literature (PMID: 31730815). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported likely pathogenic in ClinVar and in the literature in an individual with Marfan syndrome (PMID: 19533785). (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) 1207 - Parental origin of the variant is unresolved. Mother does not have the variant. Father was not tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Labcorp Genetics |
RCV005213236 | SCV005856367 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-05-21 | 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 100 of the FBN1 protein (p.Cys100Tyr). 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: 19533785; Invitae). ClinVar contains an entry for this variant (Variation ID: 228262). 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. |