ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.772C>T (p.Arg258Cys)

dbSNP: rs797044578
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000192143 SCV002769196 pathogenic Alexander disease 2020-05-12 criteria provided, single submitter clinical testing 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.
Athena Diagnostics RCV002472960 SCV002770684 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including at least one apparent de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant showed protein aggregate formation in vitro in multiple human cell types (PMID: 30213442).
GeneReviews RCV000192143 SCV000223006 not provided Alexander disease no assertion provided literature only

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