ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.716G>A (p.Arg239His)

dbSNP: rs59565950
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000056899 SCV000321721 pathogenic not provided 2020-04-30 criteria provided, single submitter clinical testing Reported previously in the heterozygous state in at least one individual with Alexander syndrome (Brenner et al., 2001); Published functional studies demonstrate that mice harboring the R239H variant develop astrocyte pathology typical of Alexander disease (Hagerman et al., 2006; Sosunov et al., 2013; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32180488, 11138011, 31484723, 28882119, 23432455, 24102621, 27966545, 27193225, 28359321, 27609520, 27798231, 27648269, 23616550, 17065456)
Laboratory for Animal Genetics, Ghent University RCV000017551 SCV000607713 pathogenic Alexander disease criteria provided, single submitter in vivo Similar disease in dogs: OMIA 001208-9615. Tetraplegia with spastic front limbs mimicking 'swimming puppy syndrome'; detection of GFAP containing Rosenthal fibers in astrocytes; Alexander's disease (AxD) in a Labrador retriever is caused by a heterozygous de novo dominant R240H GFAP mutation, orthologous to the human R239H hotspot mutation known to cause a severe AxD phenotype.
CeGaT Center for Human Genetics Tuebingen RCV000056899 SCV001746291 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing
DASA RCV000017551 SCV002526391 pathogenic Alexander disease 2022-06-10 criteria provided, single submitter clinical testing The c.716G>A;p.(Arg239His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 16168; NBK1172; OMIM 137780.0001; PMID: 24427505; 17383133; 11567214; 21533827) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 17065456, 23432455 ) - PS3. This variant is not present in population databases:rs59565950, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in GFAP that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
OMIM RCV000017551 SCV000037823 pathogenic Alexander disease 2005-03-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056899 SCV000088012 not provided not provided no assertion provided not provided
GeneReviews RCV000017551 SCV000222998 not provided Alexander disease no assertion provided literature only

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