17-44911287-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_002055.5(GFAP):c.1076T>C(p.Leu359Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L359V) has been classified as Uncertain significance.
Frequency
Consequence
NM_002055.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.1076T>C | p.Leu359Pro | missense_variant | 6/9 | ENST00000588735.3 | |
GFAP | NM_001363846.2 | c.1076T>C | p.Leu359Pro | missense_variant | 6/10 | ||
GFAP | NM_001242376.3 | c.1076T>C | p.Leu359Pro | missense_variant | 6/7 | ||
GFAP | NM_001131019.3 | c.1076T>C | p.Leu359Pro | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFAP | ENST00000588735.3 | c.1076T>C | p.Leu359Pro | missense_variant | 6/9 | 1 | NM_002055.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 359 of the GFAP protein (p.Leu359Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alexander disease (PMID: 17509491, 17894839, 18388212). ClinVar contains an entry for this variant (Variation ID: 66430). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu359 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15732097, 22566711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
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