ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5699G>A (p.Cys1900Tyr) (rs794728237)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181547 SCV000233850 pathogenic not provided 2014-08-14 criteria provided, single submitter clinical testing p.Cys1900Tyr (TGT>TAT): c.5699 G>A in exon 47 of the FBN1 gene (NM_000138.4)The C1900Y mutation in the FBN1 gene has been reported in association with Marfan syndrome (Baetens M et al., 2011; Arbustini E et al., 2005; Attanasio M et al., 2008). Attanasio et al. (2008) reported one individual who met the Ghent criteria for Marfan syndrome, whose features included: pectus carinatum, pes planus, positive wrist and thumb sign, dilation of the ascending aorta, MVP, ectopia lentis and striae. Arbustini et al. (2005) described two patients with C1900Y who met the Ghent criteria for Marfan syndrome. Patient one had aortic root dilation, MVP, ectopia lentis and skeletal findings. Patient two had dural ectasia, skin, eye and skeletal findings without major cardiac findings. C1900Y results in a non-conservative amino acid substitution of Cysteine at a position that is conserved across species. Other mutations affecting the same residue (C1900F, C1900S) and mutations affecting nearby residues (C1895R, C1895Y, G1903Y, G1903R, C1905R) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the C1900Y mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, C1900Y in the FBN1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s).
Invitae RCV000556126 SCV000627939 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1900 of the FBN1 protein (p.Cys1900Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Marfan syndrome (PMID: 16222657) and has been reported in several individuals with Marfan syndrome (PMID: 21542060, 18435798, 16222657). ClinVar contains an entry for this variant (Variation ID: 200066). 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 disrupts the p.Cys1900 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 22772377, 19839986), which suggests that this may be a clinically significant amino acid residue. 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.
Center for Medical Genetics Ghent,University of Ghent RCV000663808 SCV000787160 pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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