ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1846G>A (p.Glu616Lys) (rs397515764)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035128 SCV000058768 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing The p.Glu616Lys variant has been reported in an individual meeting Ghent clinica l criteria for Marfan syndrome (Stheneur 2009) and is reported in ClinVar (Varia tion ID: 42294). In addition, this variant has been identified by our laboratory in 2 individuals. In one family it segregated with 2 affected individuals; howe ver, in the other family it was absent in two affected first degree relatives. T his variant was absent from large population studies. Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Crite ria applied: PM2; PP3;PP4.
Invitae RCV000459707 SCV000544913 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 616 of the FBN1 protein (p.Glu616Lys). 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 (rs397515764, ExAC no frequency). This variant has been reported in an individual affected with Marfan syndrome (PMID: 19293843). This variant has also been reported in individuals in the Universal Mutation Database (PMID: 12938084). ClinVar contains an entry for this variant (Variation ID: 42294). 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. 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.
GeneDx RCV000493016 SCV000583182 likely pathogenic not provided 2015-08-26 criteria provided, single submitter clinical testing The E616K likely pathogenic variant in the FBN1 gene has been reported previously in one individual with Marfan syndrome and was absent from 200 control alleles (Stheneur et al., 2009). Furthermore, the E616K 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. The E616K 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, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. 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). Although the E616K variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, a missense variant in the same residue (E616G) and variants in nearby residues (C611R, D613N, C617G, C623G) have been reported in the Human Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Ambry Genetics RCV000621338 SCV000738854 uncertain significance Cardiovascular phenotype 2016-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000035128 SCV000919345 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: FBN1 c.1846G>A (p.Glu616Lys) results in a conservative amino acid change located in one of the EGF-like calcium-binding domains (IPR001881) 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 246196 control chromosomes (gnomAD). c.1846G>A has been reported in the literature and in a database in individuals affected with Marfan Syndrome (Stheneur_2009, Lerner-Ellis_2014, UMD database). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 likely pathogenic, 2 VUS). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000663503 SCV000786803 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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