ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1147G>A (p.Glu383Lys) (rs794728325)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181682 SCV000233985 uncertain significance not provided 2016-12-08 criteria provided, single submitter clinical testing The E383K variant of uncertain significance in the FBN1 gene has been reported previously in one individual diagnosed with classic Marfan syndrome (Loeys et al., 2001), and in another individual with features of Marfan syndrome who experienced aortic dissection before the age of 40 (Soylen et al., 2009). In addition, a missense variant in this same residue (E383Q) has been reported in association with Marfan syndrome (Soylen et al., 2009). Furthermore, E383K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E383K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs in the TGF-beta binding domain 2 at a position that is conserved across in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, the E383K variant does not affect a Cysteine residue and is not located within a calcium-binding EGF-like domain of the FBN1 gene. 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, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Invitae RCV000791430 SCV000283603 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 383 of the FBN1 protein (p.Glu383Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant also falls at the last nucleotide of exon 10 of the FBN1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Marfan syndrome (PMID: 19159394, 11700157). ClinVar contains an entry for this variant (Variation ID: 200177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Nucleotide substitutions within 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 is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. The observation of one or more missense substitutions at this codon (p.Glu383Lys and p.Glu383Gln) in affected individuals suggests that this may be a clinically significant residue (PMID: 19159394, 11700157, Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000622850 SCV000741580 likely pathogenic Inborn genetic diseases 2016-07-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Center for Medical Genetics Ghent,University of Ghent RCV000231553 SCV000786734 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.