ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3977G>A (p.Cys1326Tyr) (rs1555397738)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498455 SCV000589808 likely pathogenic not provided 2016-03-28 criteria provided, single submitter clinical testing The C1326Y variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in approximately 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. The C1326Y variant is conserved across species, and is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C1326Y variant affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). In addition, one missense variant in the same residue (C1326R) has been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this residue.Therefore, this variant is likely pathogenic
Invitae RCV000811859 SCV000952148 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1326 of the FBN1 protein (p.Cys1326Tyr). 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 not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 432123). 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.Cys1326 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10486319, 29357934), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663680 SCV000787011 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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