Submissions for variant NM_000138.5(FBN1):c.1147G>A (p.Glu383Lys)

dbSNP: rs794728325

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000231553	SCV005387645	likely pathogenic	Marfan syndrome	2024-05-23	reviewed by expert panel	curation	The NM_00138 c.1147G>A is a missense variant in FBN1 predicted to cause a substitution of a glutamic acid by lysine at amino acid 383 (p.Glu383Lys). This variant was found in a proband with a systemic score >7 and thoracic aortic aneurysm and/or dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 11700157, internal lab data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, once as likely pathogenic, and twice as uncertain significance (Variation ID: 200177). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant has been reported in the literature in at least three individuals with clinical features of MFS and/or thoracic aortic aneurysm and dissection (PS4_Mod; PMID 19159394, Invitae ClinVar entry, internal lab data) and in an individual with left iliac aneurysm (GeneDx internal lab data). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.702). This variant is located in the last nucleotide of exon 9. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM2_Sup, PP2, PP3, PP4
GeneDx	RCV000181682	SCV000233985	uncertain significance	not provided	2020-01-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 200177; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 19370756, 11700157, 19159394)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791430	SCV000283603	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-31	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 383 of the FBN1 protein (p.Glu383Lys). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 11700157, 19159394; Invitae). ClinVar contains an entry for this variant (Variation ID: 200177). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002453647	SCV002613376	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-11-13	criteria provided, single submitter	clinical testing	The p.E383K variant (also known as c.1147G>A), located in coding exon 9 of the FBN1 gene, results from a G to A substitution at nucleotide position 1147. The amino acid change results in glutamic acid to lysine at codon 383, an amino acid with similar properties, and is located in the TGFB#01 domain. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. This alteration has also been reported in Marfan syndrome cohorts (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000231553	SCV000786734	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing