Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181491 | SCV000233794 | likely pathogenic | not provided | 2017-01-03 | criteria provided, single submitter | clinical testing | The D1199G likely pathogenic variant in the FBN1 gene has been previously reported in at least two individuals who both fulfilled Ghent diagnostic criteria for Marfan syndrome (Proost et al., 2015; Somers et al., 2016); however, further clinical details or segregation studies studies were not reported. This variant has also been observed in one other individual referred for Marfan/TAAD genetic testing at GeneDx, although this individual harbored additional variants and no segregation data is available. The D1199G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D1199G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, D1199G occurs at a site within a calcium-binding EGF-like domain of fibrillin-1 that is predicted to play a role in calcium-binding. Substitution of a calcium-binding residue within a calcium-binding EGF-like domain of fibrillin-1 is recognized as a mutational mechanism for Marfan syndrome (Loeys et al., 2010). Moreover, a likely pathogenic missense variant at the same residue (D1199A) has been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this residue.Therefore, this variant is likely pathogenic |
| Labcorp Genetics |
RCV000818040 | SCV000958632 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2020-02-28 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant has been observed in individuals affected with Marfan syndrome or clinical features of this condition (PMID: 25907466, 27112580, Invitae). ClinVar contains an entry for this variant (Variation ID: 200020). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 1199 of the FBN1 protein (p.Asp1199Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant disrupts the p.Asp1199 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 22772377), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Centre of Medical Genetics, |
RCV002245984 | SCV002025283 | likely pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS6, PP4 |