ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1427G>A (p.Cys476Tyr)

dbSNP: rs2043792070
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001245896 SCV001419220 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-08-17 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 476 of the FBN1 protein (p.Cys476Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 27611364; Invitae). ClinVar contains an entry for this variant (Variation ID: 970337). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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). This variant disrupts the p.Cys476 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 7951214, 21932315; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004619587 SCV005113145 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-06-13 criteria provided, single submitter clinical testing The p.C476Y variant (also known as c.1427G>A), located in coding exon 11 of the FBN1 gene, results from a G to A substitution at nucleotide position 1427. The cysteine at codon 476 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF4 domain (Ambry internal data). This alteration has been reported in individuals with Marfan syndrome (Yang H et al. Sci Rep, 2016 Sep;6:33002; Fuentevilla-Álvarez G et al. Biomol Biomed, 2024 Mar;24:302-314). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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