ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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 RCV000231553 SCV000283603 likely pathogenic Marfan syndrome 2016-01-06 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 highly conserved and there is a small physicochemical difference between glutamic acid and lysine. It also falls at the last nucleotide of exon 10 of the FBN1 coding sequence. The majority of exons have a glycine at this position (PMID: 9536098). This variant is not present in population databases (rs794728325, ExAC no frequency). This variant has been reported in individuals affected with Marfan syndrome (PMID: 11700157, 19159394). In addition, a different variant affecting this nucleotide has been reported in a patient affected with Marfan syndrome (PMID: 19159394), indicating that this nucleotide may be crucial for normal mRNA splicing. ClinVar contains an entry for this variant (Variation ID: 200177). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is absent from population databases and several individuals with Marfan syndrome have been observed with variants affecting this conserved nucleotide. In the absence of confirmed segregation data or functional studies, this variant has been classified as Likely Pathogenic.

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