ClinVar Miner

Submissions for variant NM_002055.5(GFAP):c.1246C>T (p.Arg416Trp)

dbSNP: rs121909717
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000017552 SCV000680243 pathogenic Alexander disease 2017-10-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV001267511 SCV001445692 pathogenic Inborn genetic diseases 2019-11-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000056848 SCV002246484 pathogenic not provided 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the GFAP protein (p.Arg416Trp). This variant is present in population databases (rs121909717, gnomAD 0.01%). This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 27814755). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16169). 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: 16826512). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000017552 SCV002767965 pathogenic Alexander disease 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Fuctional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, where the latter is the more widely accepted mechanism (OMIM, GeneReviews, PMID: 11138011, PMID: 30355500, PMID: 31484723). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated tail domain (PMID: 31611638). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and shown to be de novo in a patient with Alexander disease (ClinVar). It has also been reported in multiple other patients with infantile-, juvenile- and adult-onset Alexander disease, both familial and sporadic (PMID: 31611638, PMID: 18684770, PMID: 27814755). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity RCV000017552 SCV003818146 pathogenic Alexander disease 2022-11-08 criteria provided, single submitter clinical testing
OMIM RCV000017552 SCV000037824 pathogenic Alexander disease 2006-08-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056848 SCV000087961 not provided not provided no assertion provided not provided
GeneReviews RCV000017552 SCV000223052 not provided Alexander disease no assertion provided literature only

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