Submissions for variant NM_002055.5(GFAP):c.613G>A (p.Glu205Lys)

dbSNP: rs267607507

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192127	SCV002819901	likely pathogenic	Alexander disease	2023-10-18	criteria provided, single submitter	clinical testing	Variant summary: GFAP c.613G>A (p.Glu205Lys) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.613G>A has been reported in the literature in at-least two individuals in a series affected with features of adult onset Alexander Disease (example, Pareyson_2008). However, the authors report that one of these two individuals was asymptomatic, normal neurological examination and no symptoms of Alexander Disease. These data do not allow any conclusion about variant significance. At our laboratory, this variant was observed in an adult individual and the mother, both of whom had clinical and/or MRI findings supporting a diagnosis of Alexander Disease as communicated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000056889	SCV003442439	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. ClinVar contains an entry for this variant (Variation ID: 66488). This missense change has been observed in at least one individual who was not affected with GFAP-related conditions (Invitae). This missense change has been observed in individual(s) with Alexander disease (PMID: 18684770). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 205 of the GFAP protein (p.Glu205Lys).
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056889	SCV000088002	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000192127	SCV000222988	not provided	Alexander disease		no assertion provided	literature only