Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000208295 | SCV004218518 | pathogenic | Marfan syndrome | 2023-12-29 | reviewed by expert panel | curation | NM_000138.5 c.4330T>A is a missense variant in FBN1 predicted to cause a substitution of a cysteine by serine at amino acid 1444 (p.Cys1444Ser). This variant has been identified in an adult patient with Marfan syndrome with bilateral ectopia lentis (EL), borderline thoracic aortic aneurysm and dissection (TAAD), and systemic features (PP4; Invitae internal data). A different nucleotide substitution (c.4331G>C) resulting in the same amino acid change has been identified in three individuals with clinical diagnoses of Marfan syndrome, all of whom were noted to have have EL in addition to other features of Marfan syndrome (PS4_moderate; University of Tokyo, Bichat, & Invitae internal data); in one family, c.4331G>C was found to segregate with annuloaortic ectasia and arachnodactyly in an infant child (University of Tokyo internal data). Of note, there is no predicted difference in splicing patterns between the two nucleotide substitutions. The c.4330T>A variant is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org, v2.1.1 & v3.1.2). It affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis further support that this variant is likely to impact the protein (PP3; REVEL = 0.949). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, c.4330T>A (p.Cys1444Ser) meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_moderate, PP2, PP3, PP4, PM2_supporting. |
Blueprint Genetics | RCV000208295 | SCV000263901 | uncertain significance | Marfan syndrome | 2015-11-10 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000818296 | SCV000958899 | pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2021-05-05 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Cys1444 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 31098894, Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. 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). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 222604). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 1444 of the FBN1 protein (p.Cys1444Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. |