Description
A heterozygous missense variant, NM_002055.4(GFAP):c.772C>T, has been identified in exon 4 of 9 of the GFAP gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 258 of the protein (NP_002046.1:p.Arg258Cys). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within Coil 2A of the rod functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. This variant has been reported as pathogenic in multiple patients with Alexander disease (ClinVar, Jost, M., et al. (2017)). Additionally, transfected HeLa and US-OS cells showed abnormal protein aggregates, where significantly more cells contained these aggregates compared to controls (Tulyeu, J., et al. (2019)). A different variant in the same codon resulting in a change to proline, has also been reported in a patient with Alexander disease (ClinVar, Brenner, M., et al. (2001)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
