ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.1157A>T (p.Asn386Ile)

dbSNP: rs61726471
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000056842 SCV000582051 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing The N386I variant has been published previously as an apparently de novo occurrence in association with Alexander disease (Caceres-Marzal et al., 2006). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N386I 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown N386I disrupts the filament assembly and solubility of the GFAP protein (Chen et al., 2011). Missense variants in the same codon (N386S) nearby residues (T383I, S385F) have been reported in the Human Gene Mutation Database in association with Alexander disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056842 SCV000087955 not provided not provided no assertion provided not provided
GeneReviews RCV000192181 SCV000223047 not provided Alexander disease no assertion provided literature only

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