ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.8015G>A (p.Cys2672Tyr)

dbSNP: rs1555393831
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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 RCV003767940 SCV004570915 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-04-28 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Cys2672 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28321935), 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). 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. ClinVar contains an entry for this variant (Variation ID: 549449). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 26787436). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2672 of the FBN1 protein (p.Cys2672Tyr).
Center for Medical Genetics Ghent, University of Ghent RCV000664006 SCV000787390 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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