rs267607512
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_002055.5(GFAP):c.1126C>T(p.Arg376Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376G) has been classified as Pathogenic.
Frequency
Consequence
NM_002055.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.1126C>T | p.Arg376Trp | missense_variant, splice_region_variant | 6/9 | ENST00000588735.3 | |
GFAP | NM_001363846.2 | c.1126C>T | p.Arg376Trp | missense_variant, splice_region_variant | 6/10 | ||
GFAP | NM_001242376.3 | c.1126C>T | p.Arg376Trp | missense_variant, splice_region_variant | 6/7 | ||
GFAP | NM_001131019.3 | c.1126C>T | p.Arg376Trp | missense_variant, splice_region_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFAP | ENST00000588735.3 | c.1126C>T | p.Arg376Trp | missense_variant, splice_region_variant | 6/9 | 1 | NM_002055.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg376 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 21917775), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects GFAP protein function (PMID: 27648269). This variant has been observed in individual(s) with Alexander disease (PMID: 18217876, 21533827, 23149175, 27468269, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66443). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 376 of the GFAP protein (p.Arg376Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Published functional studies suggest a damaging effect (Boczek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23149175, 18217876, 27648269, 21533827, 21917775) - |
Alexander disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at