Submissions for variant NM_002055.5(GFAP):c.1111G>A (p.Glu371Lys)

dbSNP: rs267607526

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001563640	SCV001786625	pathogenic	Alexander disease	2020-12-11	criteria provided, single submitter	clinical testing	The GFAP c.1111G>A (p.Glu371Lys) variant is a missense variant located within the Coil 2B region of the alpha-helical rod domain of the protein. The p.Glu371Lys variant has not been reported in the literature in association with Alexander disease. However, three different variants at the same amino acid position have been reported in two studies in individuals affected with Alexander disease (Kawai et al. 2005; Prust et al. 2011). The p.Glu371Lys variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the absence from population frequency databases, the location in a mutational hotspot of a functional domain and the identification in a de novo state, the p.Glu371Lys variant is classified as pathogenic for Alexander disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002569019	SCV002956346	uncertain significance	not provided	2022-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 371 of the GFAP protein (p.Glu371Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alexander disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 1199219). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Glu371 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 16168595, 26478912), which suggests that this may be a clinically significant amino acid residue. 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.