Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003476877 | SCV004218521 | likely pathogenic | Marfan syndrome | 2023-12-29 | reviewed by expert panel | curation | NM_000138.5 c.4526A>G is a missense variant in FBN1 predicted to cause a substitution of a tyrosine by cysteine at amino acid 1509 (p.Tyr1509Cys). This variant has been identified in at least four individuals including two probands with clinical diagnoses of Marfan syndrome, an individual with mild thoracic aortic aneurysm and dissection (TAAD) and systemic features without fulfilling Marfan syndrome diagnostic criteria, and an individual of tall stature with TAAD (PS4_moderate; PMID: 26787436; Johns Hopkins & University of Tokyo internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/ v2.1.1 & v3.1.2). This variant introduces a novel cysteine residue which may impede the normal formation of essential disulfide bridges and occurs at a residue in a critical calcium-binding site within a calcium-binding EGF-like domain (PM1). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.916). 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, PS4_moderate, PP2, PP3, PM2_supporting. |
| Invitae | RCV001376801 | SCV001573972 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1509 of the FBN1 protein (p.Tyr1509Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 26787436). ClinVar contains an entry for this variant (Variation ID: 180355). 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%. 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. |
| Ambry Genetics | RCV000157229 | SCV002639797 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.Y1509C variant (also known as c.4526A>G), located in coding exon 36 of the FBN1 gene, results from an A to G substitution at nucleotide position 4526. The tyrosine at codon 1509 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #22 domain. 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). This variant was reported in two individuals from a Marfan syndrome cohort, although clinical details were limited (Franken R et al. Eur Heart J, 2016 Nov;37:3285-3290). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, Y1509C disrupts a conserved region near the calcium-binding motif and a disulfide bond in a key cbEGF-like domain of FBN1 (Handford PA et al. Nature, 1991 May;351:164-7; Lee SS et al. Structure, 2004 Apr;12:717-29). 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. |
| Blueprint Genetics | RCV000157229 | SCV000206954 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2014-05-05 | no assertion criteria provided | clinical testing |