NM_002055.5(GFAP):c.197G>A (p.Arg66Gln) AND Alexander disease

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Mar 22, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000192097.17

Allele description [Variation Report for NM_002055.5(GFAP):c.197G>A (p.Arg66Gln)]

NM_002055.5(GFAP):c.197G>A (p.Arg66Gln)

Gene:

GFAP:glial fibrillary acidic protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_002055.5(GFAP):c.197G>A (p.Arg66Gln)

HGVS:

NC_000017.11:g.44915290C>T
NG_008401.1:g.5257G>A
NM_001131019.3:c.197G>A
NM_001242376.3:c.197G>A
NM_001363846.2:c.197G>A
NM_002055.5:c.197G>AMANE SELECT
NP_001124491.1:p.Arg66Gln
NP_001229305.1:p.Arg66Gln
NP_001350775.1:p.Arg66Gln
NP_002046.1:p.Arg66Gln
NP_002046.1:p.Arg66Gln
NC_000017.10:g.42992658C>T
NM_002055.3:c.197G>A
NM_002055.4:c.197G>A
P14136:p.Arg66Gln

Protein change:

R66Q

Links:

UniProtKB: P14136#VAR_071518; dbSNP: rs797044569

NCBI 1000 Genomes Browser:

rs797044569

Molecular consequence:

NM_001131019.3:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242376.3:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363846.2:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002055.5:c.197G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Alexander disease (ALXDRD)
Synonyms:: Alexanders leukodystrophy; Megalencephaly in infancy accompanied by progressive spasticity and dementia; Alexander's disease
Identifiers:: MONDO: MONDO:0008752; MedGen: C0270726; Orphanet: 58; OMIM: 203450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222951	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 22619055, 24188966, 21917775
SCV001522434	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 14, 2020)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22619055, 24188966, 21917775, 25741868
SCV002318467	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21917775, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000222951

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV001522434

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 14, 2020)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002318467

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Adult-onset Alexander disease with an R66Q mutation in GFAP presented with severe vocal cord paralysis during sleep.

Hida A, Ishiura H, Arai N, Fukuoka H, Hasuo K, Goto J, Uesaka Y, Tsuji S, Takeuchi S.

J Neurol. 2012 Oct;259(10):2234-6. doi: 10.1007/s00415-012-6540-4. Epub 2012 May 23. No abstract available.

PubMed [citation]

PMID:: 22619055

Adult onset Alexander disease presenting with progressive spastic paraplegia.

Pedroso JL, Raskin S, Barsottini OG, Oliveira AS.

Parkinsonism Relat Disord. 2014 Feb;20(2):241-2. doi: 10.1016/j.parkreldis.2013.10.014. Epub 2013 Oct 22. No abstract available.

PubMed [citation]

PMID:: 24188966

See all PubMed Citations (4)

Details of each submission

From GeneReviews, SCV000222951.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001522434.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002318467.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2025

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