chr17-44913334-G-A

Variant names:

• chr17-44913334-G-A
• rs58064122
• NM_002055.5:c.715C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.715C>T​(p.Arg239Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001786626: "The p.Arg239Cys variant has been shown to affect GFAP solubility and the organization of GFAP networks (Hsiao et al. 2005). Western blotting and whole-cell patch clamp recordings have also suggested that glutamate uptake is reduced in variant-expressing astrocytes (Tian et al. 2010)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 6.27
• Publications: 73 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786626: "The p.Arg239Cys variant has been shown to affect GFAP solubility and the organization of GFAP networks (Hsiao et al. 2005). Western blotting and whole-cell patch clamp recordings have also suggested that glutamate uptake is reduced in variant-expressing astrocytes (Tian et al. 2010)."; SCV002769076: Functional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, however, the latter is the most widely accepted mechanism (OMIM, GeneReviews, PMIDs: 11138011, 30355500, 31484723).; SCV003934815: "At least one publication reports experimental evidence showing the variant is associated with impaired autophagy leading to abnormal GFAP protein accumulation in Alexander disease (Tang_2008)."; SCV004046039: Experimental evidence suggests that the c.715C>T (p.Arg239Cys) variant affects the stability of the GFAP protein and compromises glutamate transport in astrocytes (PMID: 20448479, 15840648).; SCV004047532: Functional studies indicate R239C affects the stability of GFAP protein, altering the normal solubility and organization of GFAP networks, and leading to compromised glutamate transport in astrocytes (Hsia et al., 2005).; SCV000321720: Published functional studies demonstrate a damaging effect (PMID: 20448479; PMID: 30213442); SCV005361827: "The GFAP c.715C>T variant is predicted to result in the amino acid substitution p.Arg239Cys... in vitro functional studies suggest that the p.Arg239Cys variant may impair the filament organization, decrease solubility of GFAP, and affect glutamate transport (Hsiao et al. 2005. PubMed: 15840648; Tian et al. 2010. PubMed: 20448479)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 chr17-44913333-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-44913334-G-A is Pathogenic according to our data. Variant chr17-44913334-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 4 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.715C>T	p.Arg239Cys	missense	Exon 4 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.715C>T	p.Arg239Cys	missense	Exon 4 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 4 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1869C>T		non_coding_transcript_exon	Exon 2 of 5
	GFAP	ENST00000588957.5	TSL:3	c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 5	ENSP00000465565.1	K7EKD1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Alexander disease (11)
2	-	-	not provided (3)
1	-	-	GFAP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.98		Gain of catalytic residue at Q241 (P = 0.0165)
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.96
Mutation Taster		=2/98	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: rs58064122; hg19: chr17-42990702;