17-44915290-C-T

Variant names:

• chr17-44915290-C-T
• rs797044569
• NM_002055.5:c.197G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_002055.5(GFAP):​c.197G>A​(p.Arg66Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 4.14
• Publications: 6 publications found

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]

GFAP Gene-Disease associations (from GenCC):

• Alexander disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44915291-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1308545.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 17-44915290-C-T is Pathogenic according to our data. Variant chr17-44915290-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190332.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Mar 13, 2020

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Identified in multiple patients with features consistent with Alexander Disease, including one individual with Rosenthal fibers identified postmortem. Rosenthal fibers are the pathognomonic feature of the astrocyte pathology in Alexander Disease. Thus, this highly specific finding is suggestive of this variants pathogenicity. -

Oct 05, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on GFAP assembly and filament formation (Fu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29421207, 24188966, 22619055, 36088400, 37396762, 32374915, 34012265, 21917775) -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the GFAP protein (p.Arg66Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of adult-onset Alexander disease (PMID: 21917775, 22619055, 24188966; internal data). ClinVar contains an entry for this variant (Variation ID: 190332). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GFAP protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Alexander disease Pathogenic:1 Uncertain:1 Other:1

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GFAP related disorder (PMID:21917775). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372607). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887>=0.6). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 14, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with adult-onset Alexander disease [PMID: 22619055, 24188966, 21917775, ClinVar ID: 190332] -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;M;M;.;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.027	.;.;D;D;.;D;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.69, 0.76, 0.84
MutPred		0.83		Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);
MVP		1.0
MPC		0.58
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.0033	Neutral
Varity_R		0.95
gMVP		0.96
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044569; hg19: chr17-42992658;