Submissions for variant NM_000138.5(FBN1):c.4096G>A (p.Glu1366Lys)

dbSNP: rs763449629

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181508	SCV000233811	pathogenic	not provided	2023-07-28	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: 21895641, 25907466, 17657824, 27611364, 24199744, 31098894, 32123317, 14695540, 35058154, 34818515, 35237611, 20591885, 27724990, 33844962, DumanliA2020[Article], 16342915, 31754721, Fan2009[Abstract], 33576469)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588449	SCV000695533	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4096G>A (p.Glu1366Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.4096G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome to include a De-novo mode of inheritance reported in some (example, Baumgartner_2005, Biggin_2004, Comeglio_2007, Robinson_2011, Pees_2013, Proost_2015, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770671	SCV000902130	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-03-22	criteria provided, single submitter	clinical testing
Invitae	RCV001224814	SCV001397037	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-13	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 1366 of the FBN1 protein (p.Glu1366Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 14695540, 16342915, 17657824, 24199744, 27611364, 27724990, 31098894). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200036). 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.
Centre of Medical Genetics, University of Antwerp	RCV000663695	SCV002025298	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
Ambry Genetics	RCV000770671	SCV002632067	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-11-06	criteria provided, single submitter	clinical testing	The p.E1366K pathogenic mutation (also known as c.4096G>A), located in coding exon 33 of the FBN1 gene, results from a G to A substitution at nucleotide position 4096. The glutamic acid at codon 1366 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like domain #19. This variant has been reported in classical Marfan syndrome cases and in individuals with ectopia lentis and skeletal findings but who lacked typical cardiac findings (Biggin A et al. Hum Mutat, 2004 Jan;23:99; Comeglio P et al. Hum Mutat, 2007 Sep;28:928; Baumgartner C et al. Methods Inf Med, 2005;44:487-97; Pees C et al. Clin Genet, 2014 Dec;86:552-7; Proost D et al. Hum Mutat, 2015 Aug;36:808-14). This variant was more recently reported as de novo in a child with ectopia lentis and mild aortic dilation (Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637). This variant was not reported in population-based 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.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000181508	SCV002818161	likely pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663695	SCV000787027	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing