Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001850427 | SCV002247461 | pathogenic | not provided | 2022-08-31 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val87 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 21533827, 24306001), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 190339). This missense change has been observed in individuals with Alexander disease (PMID: 21533827, 24306001; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 87 of the GFAP protein (p.Val87Ile). |
Lifecell International Pvt. |
RCV000192117 | SCV003915940 | pathogenic | Alexander disease | criteria provided, single submitter | clinical testing | A Heterozygous Missense variant c.259G>A in Exon 1 of the GFAP gene that results in the amino acid substitution p.Val87Ile was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(variant ID 190339). This variant has been observed in many individuals affected with Alexander disease reported by (Srivastava S, et al., 1993). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. | |
Gene |
RCV000192117 | SCV000222976 | pathogenic | Alexander disease | 2015-01-08 | no assertion criteria provided | literature only |