Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000663461 | SCV005387650 | likely pathogenic | Marfan syndrome | 2024-05-23 | reviewed by expert panel | curation | The NM_00138 c.1468G>T is a missense variant in FBN1 predicted to cause a substitution of a aspartic acid by tyrosine at amino acid 490 (p.Asp490Tyr). This variant impacts an aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (PMID 35058154, internal lab data, PP4). This variant has been reported three times in ClinVar: twice as pathogenic and once as uncertain significance (Variation ID: 549019). This variant has also been identified in at least 2 individuals with a clinical diagnosis of MFS as well as in an individual with clinical features of MFS (PMID 11826022, 20886638, Invitae ClinVar entry; PS4_Mod). A different missense variant at this position, c.1468G>C (p.Asp490His), has previously been previously established as (likely) pathogenic and has been found in at least 3 individuals with clinical features of MFS and was found to segregate with disease (PMID 25652356, internal data; PM5), Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.965, PP3). This variant is located in the last nucleotide of the exon. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1, PM5, PS4_Moderate, PM2_Sup, PP2, PP3, PP4. |
| Centre of Medical Genetics, |
RCV000663461 | SCV002025477 | pathogenic | Marfan syndrome | 2021-03-01 | criteria provided, single submitter | research | PM2, PS6, PP4 |
| Labcorp Genetics |
RCV003767926 | SCV004570974 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2024-01-06 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 490 of the FBN1 protein (p.Asp490Tyr). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 11826022, 20886638, 35058154; Invitae). ClinVar contains an entry for this variant (Variation ID: 549019). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Center for Medical Genetics Ghent, |
RCV000663461 | SCV000786755 | uncertain significance | Marfan syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |