ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.620A>T (p.Glu207Val)

dbSNP: rs1555574517
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498040 SCV000589810 likely pathogenic not provided 2016-03-23 criteria provided, single submitter clinical testing The E207V variant in the GFAP gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E207V variant was not observed in approximately 6500 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 E207V 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 at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Pathogenic missense variants in the same residue (E207K, E207Q) have been reported in the Human Gene Mutation Database in association with Alexander disease (Stenson et al., 2014), supporting the functional importance of this residue. The E207V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV000498040 SCV003441993 uncertain significance not provided 2022-04-08 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Glu207 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15732097). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 432125). This missense change has been observed in individual(s) with Alexander disease (PMID: 29095329). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 207 of the GFAP protein (p.Glu207Val).

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