ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7649G>A (p.Cys2550Tyr)

dbSNP: rs1555394196
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000722052 SCV000853070 pathogenic Marfan syndrome 2018-11-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535020 SCV003443563 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-07-15 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 590852). This missense change has been observed in individuals with Marfan syndrome (PMID: 24199744; Invitae). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2550 of the FBN1 protein (p.Cys2550Tyr).
GeneDx RCV005250104 SCV005900827 likely pathogenic not provided 2024-09-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a cysteine residue/Introduces a new cysteine residue] within an 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 EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084, 24199744)

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