Submissions for variant NM_000138.5(FBN1):c.7828G>A (p.Glu2610Lys)

dbSNP: rs111984349

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311119	SCV000320082	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-03-16	criteria provided, single submitter	clinical testing	The p.E2610K pathogenic mutation (also known as c.7828G>A), located in coding exon 63 of the FBN1 gene, results from a G to A substitution at nucleotide position 7828. The glutamic acid at codon 2610 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like #42 domain. This mutation has been reported in several individuals with a diagnosis of Marfan syndrome based on Ghent criteria and has been reported as de novo in several cases (Liu WO et al. Genet. Test. 1997-1998;1(4):237-42; Arbustini E et al. Hum Mutat. 2005 Nov;26(5):494; Baetens M et al. Hum Mutat. 2011;32(9):1053-62; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Becerra-Muñoz VM et al. Orphanet J Rare Dis, 2018 01;13:16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000540250	SCV000627998	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2610 of the FBN1 protein (p.Glu2610Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 10533071, 16222657, 17657824, 17701892, 21542060, 24161884). ClinVar contains an entry for this variant (Variation ID: 264272). 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. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659583	SCV000781421	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763353	SCV000894043	pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374807	SCV001439508	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Centre of Medical Genetics, University of Antwerp	RCV000659583	SCV002025464	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
GeneDx	RCV003441830	SCV004169579	pathogenic	not provided	2023-05-08	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; This variant is associated with the following publications: (PMID: 17657824, 35058154, 31098894, 33436942, 33824467, 10533071, 17701892, 16222657, 10464652, 29357934, 21542060, 27724990, 24161884, 26133393, 20591885)
Center for Medical Genetics Ghent, University of Ghent	RCV000659583	SCV000787366	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing