NM_002055.5(GFAP):c.1079A>T (p.Asp360Val) AND Alexander disease

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000192162.12

Allele description [Variation Report for NM_002055.5(GFAP):c.1079A>T (p.Asp360Val)]

NM_002055.5(GFAP):c.1079A>T (p.Asp360Val)

Genes:

LOC130060994:ATAC-STARR-seq lymphoblastoid active region 12266 [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.1079A>T (p.Asp360Val)

HGVS:

NC_000017.11:g.44911284T>A
NG_008401.1:g.9263A>T
NM_001131019.3:c.1079A>T
NM_001242376.3:c.1079A>T
NM_001363846.2:c.1079A>T
NM_002055.5:c.1079A>TMANE SELECT
NP_001124491.1:p.Asp360Val
NP_001229305.1:p.Asp360Val
NP_001350775.1:p.Asp360Val
NP_002046.1:p.Asp360Val
NP_002046.1:p.Asp360Val
NC_000017.10:g.42988652T>A
NM_002055.4:c.1079A>T

Protein change:

D360V

Links:

dbSNP: rs62636501

NCBI 1000 Genomes Browser:

rs62636501

Molecular consequence:

NM_001131019.3:c.1079A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001242376.3:c.1079A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363846.2:c.1079A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002055.5:c.1079A>T - 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
SCV000223027	GeneReviews	no assertion criteria provided	Pathogenic (Jan 8, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002059029	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID: 21533827

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000223027

GeneReviews

no assertion criteria provided

Pathogenic
(Jan 8, 2015)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV002059029

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

PMID: 21533827

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	literature only, clinical testing

Citations

PubMed

Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis.

Yoshida T, Sasaki M, Yoshida M, Namekawa M, Okamoto Y, Tsujino S, Sasayama H, Mizuta I, Nakagawa M; Alexander Disease Study Group in Japan.

J Neurol. 2011 Nov;258(11):1998-2008. doi: 10.1007/s00415-011-6056-3. Epub 2011 May 1.

PubMed [citation]

PMID:: 21533827

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneReviews, SCV000223027.1

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

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

From 3billion, SCV002059029.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GFAP related disorder (ClinVar ID: VCV000066431, PMID:21533827 PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Alexander disease (PP2_P). Therefore, this variant is classified as 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: May 3, 2025

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