Submissions for variant NM_000138.5(FBN1):c.3217G>A (p.Glu1073Lys)

dbSNP: rs137854478

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181482	SCV000233785	pathogenic	not provided	2020-04-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate increased susceptibility to proteolytic decay as compared to wild type (Reinhardt et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (E1073D) has been reported in the published literature in association with neonatal Marfan syndrome (Wang et al., 1996); Reported as pathogenic in ClinVar (ClinVar Variant ID#16457; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21784848, 10766875, 17324963, 7611299, 27914124, 8882780, 16596670, 28497657)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684781	SCV000283619	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-05-25	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. Experimental studies have shown that this missense change affects FBN1 function (PMID: 10766875, 17324963, 21784848). 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: 16457). This missense change has been observed in individuals with Marfan syndrome (PMID: 7611299, 8880577, 8882780, 11175294, 16596670). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1073 of the FBN1 protein (p.Glu1073Lys).
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	RCV002313714	SCV000738863	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-01-11	criteria provided, single submitter	clinical testing	The p.E1073K pathogenic mutation (also known as c.3217G>A), located in coding exon 26 of the FBN1 gene, results from a G to A substitution at nucleotide position 3217. The glutamic acid at codon 1073 is replaced by lysine, an amino acid with similar properties, and is located in the cb EGF-like #12 domain. This alteration has been reported in multiple neonatal Marfan syndrome (MFS) cases, several times with a likely de novo origin (Nijbroek G et al. Am. J. Hum. Genet. 1995;57:8-21; Putnam EA et al. Am. J. Med. Genet. 1996;62:233-42; Adès LC et al. Am. J. Med. Genet. A. 2006;140:1047-58; Pees C et al. Clin. Genet. 2014;86:552-7; Maeda J et al. Heart Vessels. 2016;31:1717-23; Heo JS et al. J. Korean Med. Sci. 2017;32:1-3). In addition, functional studies have suggested that protein with this alteration is more susceptible to proteolytic degradation compared to wildtype and is not effectively incorporated into the extracellular matrix (Milewicz DM et al. J. Clin. Invest. 1992;89:79-86; Reinhardt DP et al. J. Biol. Chem. 2000;275:12339-45; Kirschner R et al. J. Biol. Chem. 2011;286:32810-23). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000017920	SCV000038199	pathogenic	Neonatal Marfan syndrome	2006-05-15	no assertion criteria provided	literature only
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
Center for Medical Genetics Ghent, University of Ghent	RCV000227621	SCV000786937	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing