ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.401G>A (p.Cys134Tyr) (rs1555405043)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588574 SCV000695530 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-04-20 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "deleterious" outcome, although these predictions have yet to be functionally assessed. The variant of interest is located in the cbEGF-like domain and causes the alteration of a cysteine to a tyrosine. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage . In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in an affected individual via a publication that shown a strong family history of MFS, although additional family members were not indicated to have been genetically tested. The variant of interest has not been reported by reputable clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Likely Pathogenic.
Invitae RCV000692837 SCV000820681 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 134 of the FBN1 protein (p.Cys134Tyr). 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 reported in an individual affected with Marfan syndrome (PMID: 25101912). ClinVar contains an entry for this variant (Variation ID: 495602). 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.Cys134 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related disease (PMID: 23684891, 16835936), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663684 SCV000787015 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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