NM_002055.5(GFAP):c.236G>A (p.Arg79His) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000056869.28

Allele description [Variation Report for NM_002055.5(GFAP):c.236G>A (p.Arg79His)]

NM_002055.5(GFAP):c.236G>A (p.Arg79His)

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.236G>A (p.Arg79His)

HGVS:

NC_000017.11:g.44915251C>T
NG_008401.1:g.5296G>A
NM_001131019.3:c.236G>A
NM_001242376.3:c.236G>A
NM_001363846.2:c.236G>A
NM_002055.5:c.236G>AMANE SELECT
NP_001124491.1:p.Arg79His
NP_001229305.1:p.Arg79His
NP_001350775.1:p.Arg79His
NP_002046.1:p.Arg79His
NP_002046.1:p.Arg79His
NC_000017.10:g.42992619C>T
NM_002055.4:c.236G>A
P14136:p.Arg79His

Protein change:

R79H; ARG79HIS

Links:

UniProtKB: P14136#VAR_017468; OMIM: 137780.0004; dbSNP: rs59285727

NCBI 1000 Genomes Browser:

rs59285727

Molecular consequence:

NM_001131019.3:c.236G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242376.3:c.236G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363846.2:c.236G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002055.5:c.236G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000087982	Epithelial Biology; Institute of Medical Biology, Singapore	no classification provided	not provided	not provided	not provided
SCV000565039	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 23, 2023)	germline	clinical testing	Citation Link,
SCV001250437	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2023)	germline	clinical testing	Citation Link,
SCV003442440	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18584981, 23254569, 17065456, 23432455, 28882119, 11138011, 16168593, 31942421, 31956193, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Tumor-like enlargement of the optic chiasm in an infant with Alexander disease.

Mignot C, Desguerre I, Burglen L, Hertz-Pannier L, Renaldo F, Gadisseux JF, Gallet S, Pham-Dinh D, Boespflug-Tanguy O, Rodriguez D.

Brain Dev. 2009 Mar;31(3):244-7. doi: 10.1016/j.braindev.2008.05.005. Epub 2008 Jun 26.

PubMed [citation]

PMID:: 18584981

Magnetic resonance imaging "tigroid pattern" in Alexander disease.

Biancheri R, Rossi A, Ceccherini I, Pezzella M, Prato G, Striano P, Minetti C.

Neuropediatrics. 2013 Jun;44(3):174-6. doi: 10.1055/s-0032-1329910. Epub 2012 Dec 19.

PubMed [citation]

PMID:: 23254569

See all PubMed Citations (10)

Details of each submission

From Epithelial Biology; Institute of Medical Biology, Singapore, SCV000087982.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

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

From GeneDx, SCV000565039.5

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

Description

Published functional studies in mouse models and zebrafish demonstrate a damaging effect (Hagemann et al., 2006; Lee et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11567214, 12034785, 28882119, 31932408, 31956193, 35105675, 34950187, 34865968, 17065456, 11138011, 23364391, 23432455, 16168593, 19444543, 30134051, 31952467, 31942421, 34146839, 35231114, 35511821)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001250437.20

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

Description

GFAP: PS2, PM2, PM5, PP3, PS4:Supporting

#	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		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442440.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg79 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11138011, 18584981, 23254569, 28882119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GFAP function (PMID: 17065456, 23432455, 28882119). 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) performed at Invitae indicates that this missense variant is expected to disrupt GFAP protein function. ClinVar contains an entry for this variant (Variation ID: 16170). This variant is also known as 250G>A R79H. This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 16168593, 31942421, 31956193). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the GFAP protein (p.Arg79His).

#	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

Last Updated: Nov 3, 2024

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