ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3217G>A (p.Glu1073Lys) (rs137854478)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181482 SCV000603651 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The p.Glu1073Lys is a known pathogenic variant that has been reported mostly in patients with neonatal Marfan syndrome, but also in patients 10 months – 2 years old (Nijbroek 1995, Putnam 1996, Tiecke 2001, Loeys 2004, Ades 2006, Faivre 2009, Stheneur 2009). This variant meets Ghent criteria for causal FBN1 variants, as it disrupts glutamic acid in a calcium-binding Epidermal Growth Factor-like (cbEGF) domain (Loeys 2010). In vitro functional assays with p.Glu1073Lys variant showed normal secretion (Reinhard 2000, Whiteman 2007,) but increased proteolytic cleavage suggesting structural effects of the variant and reduced ability to interact with heparin (Reinhard 2000, Kirschner 2011), The secreted fibrillin was not incorporated into the pericellular matrix (Putnam 1996).
Ambry Genetics RCV000621924 SCV000738863 pathogenic Cardiovascular phenotype 2017-01-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Center for Medical Genetics Ghent,University of Ghent RCV000227621 SCV000786937 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000227621 SCV000692224 pathogenic Marfan syndrome 2016-05-17 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582993 SCV000692225 pathogenic Loeys-Dietz syndrome 2016-05-17 no assertion criteria provided clinical testing
GeneDx RCV000181482 SCV000233785 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing The E1073K pathogenic variant in the FBN1 gene has been reported in several individuals with neonatal Marfan syndrome (Nijbroek et al., 1995; Putnam et al., 1996; Ades et al., 2006; Heo et al., 2017). Nijbroek et al. (1995) first reported E1073K as a sporadic variant identified in a newborn with significant dolichostenomelia, arachnodactyly, scoliosis, joint contractures, crumpled ears, mitral valve prolapse and progressive aortic root dilation. Subsequently, additional patients who harbor E1073K were reported to exhibit similar features of neonatal Marfan syndrome (Putnam et al., 1996; Ades et al., 2006; Heo et al., 2017). E1073K results in a non-conservative amino acid substitution and occurs at a site within a calcium-binding EGF-like domain of fibrillin-1 that is predicted to play a role in calcium-binding. Substitution of a calcium-binding residue within a calcium-binding EGF-like domain of fibrillin-1 is recognized as a mutational mechanism for Marfan syndrome (Loeys et al., 2010). In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies indicate E1073K results in increased susceptibility to proteolytic decay as compared to wild type, thus affecting calcium binding capacity and protein stability with regard to conformational folding and intrinsic stability (Reinhardt et al., 2000). A different variant affecting the same residue (E1073D) has been reported in association with neonatal Marfan syndrome (Wang et al., 1996), further supporting the functional importance of this region of the protein. Finally, the E1073K variant is not observed in large population cohorts (Lek et al., 2016). In summary, E1073K in the FBN1 gene is interpreted as a pathogenic variant.
Invitae RCV000684781 SCV000283619 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1073 of the FBN1 protein (p.Glu1073Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Marfan syndrome (PMID:  7611299, 8880577, 8882780, 11175294, 16596670). ClinVar contains an entry for this variant (Variation ID: 16457). Experimental studies have shown that this missense change disrupts the functional folding of the FBN1 protein (PMID: 21784848, 10766875, 17324963). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017920 SCV000038199 pathogenic Marfan syndrome, neonatal 2006-05-15 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.