ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4096G>A (p.Glu1366Lys) (rs763449629)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181508 SCV000233811 likely pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The E1366K variant has been reported in individuals with a clinical diagnosis or suspected diagnosis of Marfan syndrome (Biggin A et al., 2004; Comeglio et al., 2007; Fan et al., 2009; Pees et al., 2014). Biggin et al. reported a 31 year-old patient with joint hypermobility, high arched palate, characteristic facial appearance and ectopia lentis who harbored the E1366K variant. Fan et al. (2009) reported in an abstract presented at the Annual Meeting of the American Society of Human Genetics that this variant occurred de novo in a 15-year-old female with tall stature, arachnodactyly, scoliosis, dilatation of the aortic root, mitral valve prolapse and lens subluxations who also harbored a variant in the TGFBR2 gene. Missense variants in nearby residues (C1361Y, C1367R, C1374G, C1374Y, C1374S) have been reported in association with Marfan syndrome in the Human Gene Mutation Database (Stenson P et al., 2014). Furthermore, the NHLBI Exome Sequencing Project reports E1366K was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations. However, although E1366K is located within a calcium binding EGF-like domain of the FBN1 gene, this variant does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003).Therefore, this variant is likely pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588449 SCV000695533 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The c.4096G>A (p.Glu1366Lys) in FBN1 gene is a missense change that involves a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. This change falls and potentially disrupts a conserved consensus sequence for calcium binding EGF-like module #19. The variant is absent from the control population dataset of ExAC. This variant was reported in multiple pts, who did and did not fulfill the revised Ghent criteria. The variant of interest has been reported as Likely Pathogenic by reputable databases/clinical laboratories. Taking together, 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 2018-02-28 criteria provided, single submitter clinical testing
Invitae RCV001224814 SCV001397037 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1366 of the FBN1 protein (p.Glu1366Lys). 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 observed in individual(s) with clinical features of Marfan syndrome (PMID: 14695540, 27611364, 27724990, 24199744, 17657824, 16342915, 31098894). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200036). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663695 SCV000787027 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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