ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.4531T>C (p.Cys1511Arg)

dbSNP: rs397515811
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035204 SCV000058847 likely pathogenic Marfan syndrome 2020-08-07 criteria provided, single submitter clinical testing The p.Cys1511Arg variant in FBN1 has been identified in 2 individuals with clinical features of Marfan syndrome/thoracic aortic dissection (Lerner-Ellis 2014 PubMed: 24793577; Wolford 2019 PubMed: 31211624) and was absent in large population studies. This variant is reported in ClinVar (allele ID: 842502). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). One additional variants involving this codon (p.Cys1511Phe) has been reported in aortopathy (Yang 2016 PubMed: 27611364; Li 2019 PubMed: 31098894). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM2; PM1; PM5; PS4_Supporting; PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001213084 SCV001384700 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-09-19 criteria provided, single submitter clinical testing This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 24793577, Invitae). ClinVar contains an entry for this variant (Variation ID: 42364). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 1511 of the FBN1 protein (p.Cys1511Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004619194 SCV005113149 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-04-17 criteria provided, single submitter clinical testing The p.C1511R variant (also known as c.4531T>C), located in coding exon 36 of the FBN1 gene, results from a T to C substitution at nucleotide position 4531. The cysteine at codon 1511 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been reported in subjects with features of Marfan syndrome (Lerner-Ellis JP et al. Mol Genet Metab, 2014 Jun;112:171-6; Beil A et al. BMC Med Genomics, 2021 Mar;14:66; Ambry internal data). 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 cbEGF-22 domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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