Submissions for variant NM_002055.5(GFAP):c.197G>A (p.Arg66Gln)

dbSNP: rs797044569

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001288188	SCV001475136	likely pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Identified in multiple patients with features consistent with Alexander Disease, including one individual with Rosenthal fibers identified postmortem. Rosenthal fibers are the pathognomonic feature of the astrocyte pathology in Alexander Disease. Thus, this highly specific finding is suggestive of this variants pathogenicity.
Baylor Genetics	RCV000192097	SCV001522434	uncertain significance	Alexander disease	2020-04-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with adult-onset Alexander disease [PMID: 22619055, 24188966, 21917775, ClinVar ID: 190332]
3billion, Medical Genetics	RCV000192097	SCV002318467	likely pathogenic	Alexander disease	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GFAP related disorder (PMID:21917775). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372607). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887>=0.6). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001288188	SCV005325897	likely pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on GFAP assembly and filament formation (Fu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29421207, 24188966, 22619055, 36088400, 37396762, 32374915, 34012265, 21917775)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288188	SCV005836645	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the GFAP protein (p.Arg66Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of adult-onset Alexander disease (PMID: 21917775, 22619055, 24188966; internal data). ClinVar contains an entry for this variant (Variation ID: 190332). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GFAP protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000192097	SCV000222951	not provided	Alexander disease		no assertion provided	literature only