ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.667G>C (p.Glu223Gln)

gnomAD frequency: 0.00027  dbSNP: rs56679084
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000192131 SCV001140668 uncertain significance Alexander disease 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000192131 SCV001369932 uncertain significance Alexander disease 2019-01-28 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP2,PM1,PP5.
Labcorp Genetics (formerly Invitae), Labcorp RCV000056895 SCV002294229 uncertain significance not provided 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 223 of the GFAP protein (p.Glu223Gln). This variant is present in population databases (rs56679084, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Alexander disease (PMID: 12944715). ClinVar contains an entry for this variant (Variation ID: 66494). 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. Experimental studies have shown that this missense change affects GFAP function (PMID: 19444543). 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.
CeGaT Center for Human Genetics Tuebingen RCV000056895 SCV002545940 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing GFAP: BS2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000192131 SCV002766799 likely benign Alexander disease 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of Alexander disease (MIM#203450). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Breakthrough Genomics, Breakthrough Genomics RCV000056895 SCV005192918 uncertain significance not provided criteria provided, single submitter not provided
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056895 SCV000088008 not provided not provided no assertion provided not provided
GeneReviews RCV000192131 SCV000222992 pathogenic Alexander disease 2015-01-08 no assertion criteria provided literature only

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