Submissions for variant NM_002055.5(GFAP):c.235C>T (p.Arg79Cys)

dbSNP: rs59793293

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000056868	SCV000513135	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(R79C) significantly increases GFAP aggregation in zebra fish in comparison to wild-type (Lee et al., 2017) and impairs mitochondrial transfer from astrocytes to neighboring neurons (Gao et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12509855, 23254569, 15696488, 18584981, 12034785, 12175861, 21533827, 11567214, 12581808, 15732097, 19128991, 18463287, 31484723, 33176815, 31327963, 11138011, 33084218, 34146839, 34692893, 17894839, 28882119)
Invitae	RCV000056868	SCV002227999	pathogenic	not provided	2022-08-05	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg79 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 11138011), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GFAP function (PMID: 28882119). 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: 16171). This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 18584981, 23254569). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the GFAP protein (p.Arg79Cys).
Illumina Laboratory Services, Illumina	RCV000017554	SCV004814145	pathogenic	Alexander disease	2022-07-25	criteria provided, single submitter	clinical testing	The GFAP c.235C>T p.(Arg79Cys) missense variant has been reported in a heterozygous state in at least seven individuals with Alexander disease, including five in whom it occurred in a de novo state (PMID: 11138011; PMID: 15696488; PMID: 18584981; PMID: 23254569; PMID: 31484723; PMID: 33176815). The c.235C>T variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000015 in the European (non-Finnish) population (version 3.1.2). Compared to wild-type GFAP, the p.(Arg79Cys) variant has been shown to significantly increase GFAP aggregation when expressed in zebrafish (PMID: 28882119). Mass spectroscopy studies in a patient with the variant suggested that levels of variant GFAP were lower than those of wild-type, suggesting an intrinsic toxicity of the variant form (PMID: 31484723). When expressed in human pluripotent stem cells induced to differentiate into astrocytes, the variant also impaired mitochondrial transfer from astrocytes and reduced astrocytic CD38 expression (PMID: 31327963). This variant was identified in a de novo state in the proband. Based on the available evidence, the c.235C>T (p.Arg79Cys) variant is classified as pathogenic for Alexander disease.
OMIM	RCV000017554	SCV000037826	pathogenic	Alexander disease	2007-11-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056868	SCV000087981	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000017554	SCV000222966	not provided	Alexander disease		no assertion provided	literature only