17-44910632-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_002055.5(GFAP):āc.1154C>Gā(p.Ser385Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_002055.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GFAP | NM_002055.5 | c.1154C>G | p.Ser385Cys | missense_variant | Exon 7 of 9 | ENST00000588735.3 | NP_002046.1 | |
GFAP | NM_001363846.2 | c.1154C>G | p.Ser385Cys | missense_variant | Exon 7 of 10 | NP_001350775.1 | ||
GFAP | NM_001242376.3 | c.1154C>G | p.Ser385Cys | missense_variant | Exon 7 of 7 | NP_001229305.1 | ||
GFAP | NM_001131019.3 | c.1154C>G | p.Ser385Cys | missense_variant | Exon 7 of 8 | NP_001124491.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:4
The S385C variant in the GFAP gene has been reported previously in a father and son with Alexanderdisease (Graff-Radford et al., 2014). This substitution has not been observed in approximately 6,500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The S385C variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge,size and/or other properties. Additionally, this substitution occurs at a position where amino acids with similarproperties to Serine are tolerated across species, and other missense variants nearby and at the same position(S385F) have been reported in the Human Gene Mutation Database in association with Alexander disease(Stenson et al., 2014; Zang et al., 2013). In silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, we interpret S385C as a pathogenic variant. -
GFAP: PM2, PM5, PS4:Moderate, PP3 -
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 385 of the GFAP protein (p.Ser385Cys). 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: 24306001, 26285664; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190362). 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. This variant disrupts the p.Ser385 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22818990, 23364391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
PM2, PM5, PP1, PP4 -
Alexander disease Pathogenic:2Other:1
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. The mechanism of disease for this gene is not clearly established. Functional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, however, the latter is the more widely accepted mechanism (OMIM, PMIDs: 11138011, 30355500, 31484723, 20301351).(I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301351). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the functional important C-terminal domain. Mutant constructs harbouring C-terminal GFAP variants identified in affected individuals resulted in protein self-aggregation compared to wild type GFAP protein. Co-transfection of mutant and wild type constructs also resulted in increased filament aggregation relative to the amount of mutant construct. However, these experiments were performed in cancer cell ines and may not represent the best experimental model to investigate filament assembly (PMID: 21756903). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.S385F variant has been reported in two individuals with infantile Alexander disease (PMIDs: 23364391, 22818990). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in four individuals with adult Alexander disease (PMIDs: 24306001, 26285664, Le S. and Soileau M. 2017, ClinVar). (SP) 0906 - Segregation evidence for this variant is inconclusive. There is insufficient information to determine the segregation of this variant with disease. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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 -
Variant summary: GFAP c.1154C>G (p.Ser385Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 205884 control chromosomes. c.1154C>G has been reported in the literature in individuals affected with Alexander Disease or multiple sclerosis (Graff-Radford_2014, Le_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at