ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7708G>A (p.Glu2570Lys) (rs886038786)

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
Ambry Genetics RCV000251768 SCV000317723 likely pathogenic Cardiovascular phenotype 2015-09-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Structural Evidence,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
GeneDx RCV000480933 SCV000568639 likely pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing The E2570K likely pathogenic variant in the FBN1 gene has been reported in association with Marfan syndrome in three unrelated individuals (Arbustini et al., 2005; Attanasio et al., 2008; Soylen et al., 2009). Furthermore, this variant segregated with Marfan syndrome in two affected children of one of these probands (Soylen et al., 2009). The E2570K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E2570K 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. Additionally, glutamic acid is conserved at this position across species and in all calcium-binding EGF-like domains in the FBN1 gene. E2570 is a calcium-binding residue located within a calcium-binding EGF-like domain, and loss of these residues is a well-established mechanism of disease in the FBN1 gene (Loeys et al., 2010). Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000780252 SCV000917362 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2018-09-04 criteria provided, single submitter clinical testing Variant summary: FBN1 c.7708G>A (p.Glu2570Lys) results in a conservative amino acid change located in the EGF-like domain 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 245478 control chromosomes (gnomAD and publications). c.7708G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (Arbustini_2005, Attanasio_2008, Soylen_2009). 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. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000794952 SCV000934390 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2570 of the FBN1 protein (p.Glu2570Lys). 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 to segregate with Marfan syndrome in a family (PMID: 19159394) and has been observed in several individuals with Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 16222657, 28973303, 18435798). ClinVar contains an entry for this variant (Variation ID: 263398). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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.