ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5431G>A (p.Glu1811Lys) (rs761857514)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181543 SCV000233846 likely pathogenic not provided 2015-11-16 criteria provided, single submitter clinical testing The E1811K likely pathogenic variant in the FBN1 gene has been reported in multiple patients with Marfan syndrome (Comeglio et al., 2007; Howarth et al., 2007; Attanasio et al., 2008; Lu et al., 2013). E1811K results in a non-conservative amino acid substitution at a position that is conserved across species. Missense variants in nearby residues (C1806S, D1808H, C1812R, C1812Y, C1818G) have been reported in HGMD in association with Marfan syndrome, Marfan-like syndrome and related disorders (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Furthermore, the E1811K variant 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.Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded
Invitae RCV000468318 SCV000544891 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1811 of the FBN1 protein (p.Glu1811Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant (rs761857514) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in the literature in multiple unrelated individuals affected with Marfan syndrome (PMID: 17627385, 17657824, 23744319, 18435798, 23684891). ClinVar contains an entry for this variant (Variation ID: 200063). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000587722 SCV000695558 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-04-27 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.5431G>A (p.Glu1811Lys) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). It is located 9 nucleotides downstream from intron-exon boundary and 5/5 splice prediction tools predict no significant impact on the utilization of consensus splice site; however, one tool (Human Splicing Finder) predicts creation of a de novo splice donor site. ESE finder predicts that this variant may affect ESE site of SRp40. It is located in calcium binding EGF domain 26 (InterPro) of the protein where cysteine residues are known to be critical. Other missense variants in nearby residues (C1806S, D1808H, C1812R, C1812Y, C1818G, etc.) have been reported in patients with Marfan syndrome, Marfan-like syndrome and related disorders (ref. HGMD), supporting the functional importance of this region. This variant was found in 1/121594 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). In literature, this variant is regarded as pathogenic variant and is reported in several patients (at least 8 unrelated patients) with Marfan syndrome. However, there are no cosegregation and functional studies. While one clinical lab classifies it as likely pathogenic, another classifies it as variant of unknown significance. Taken together, this variant is currently classified as likely pathogenic.
Ambry Genetics RCV000621581 SCV000738874 likely pathogenic Cardiovascular phenotype 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Medical Genetics Ghent,University of Ghent RCV000663784 SCV000787135 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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