17-44910632-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_002055.5(GFAP):c.1154C>G(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S385F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.34

Genes affected

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest Tail (size 54) in uniprot entity GFAP_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 17-44910632-G-C is Pathogenic according to our data. Variant chr17-44910632-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.1154C>G	p.Ser385Cys	missense_variant	7/9	ENST00000588735.3
GFAP	NM_001363846.2	c.1154C>G	p.Ser385Cys	missense_variant	7/10
GFAP	NM_001242376.3	c.1154C>G	p.Ser385Cys	missense_variant	7/7
GFAP	NM_001131019.3	c.1154C>G	p.Ser385Cys	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1154C>G	p.Ser385Cys	missense_variant	7/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	GFAP: PM2, PM5, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 08, 2023	For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 190362). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 18, 2020	PM2, PM5, PP1, PP4 -

Alexander disease Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2021	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;T;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.78, 0.77
MutPred		0.56		Loss of disorder (P = 0.0338);Loss of disorder (P = 0.0338);Loss of disorder (P = 0.0338);.;.;Loss of disorder (P = 0.0338);Loss of disorder (P = 0.0338);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044590; hg19: chr17-42988000;