Submissions for variant NM_002055.5(GFAP):c.382G>A (p.Asp128Asn)

dbSNP: rs267607509

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000056885	SCV002135533	pathogenic	not provided	2020-12-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GFAP protein function (PMID: 28882119). This variant has been observed in individual(s) with Alexander disease (PMID: 18684770, 28882119, 25997626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66484). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 128 of the GFAP protein (p.Asp128Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.
Lifecell International Pvt. Ltd	RCV000192126	SCV003922032	likely pathogenic	Alexander disease		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.382G>A in Exon 1 of the GFAP gene that results in the amino acid substitution p.Asp128Asn 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 high, 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: 66484).This disorder has previously been reported in the patient affected with autism (Nykamp K, et. al 2017). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056885	SCV000087998	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000192126	SCV000222987	not provided	Alexander disease		no assertion provided	literature only