NM_002055.5(GFAP):c.197G>A (p.Arg66Gln) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 15, 2024
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:: RCV001288188.12

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]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001475136	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Mar 13, 2020)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21917775, 22619055, 24188966, 29421207, 26467025
SCV005325897	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 5, 2023)	germline	clinical testing	Citation Link,
SCV005836645	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21917775, 22619055, 24188966, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001475136

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Mar 13, 2020)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005325897

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 5, 2023)

germline

clinical testing

Citation Link,

SCV005836645

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 15, 2024)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	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

Citations

PubMed

[An atypical presentation of Infantile Alexander disease lacking macrocephaly].

Esmer C, Villegas-Aguilera M, Morales-Ibarra JJ, Bravo-Oro A.

Bol Med Hosp Infant Mex. 2016 May-Jun;73(3):196-201. doi: 10.1016/j.bmhimx.2016.02.005. Epub 2016 May 31. Spanish.

PubMed [citation]

PMID:: 29421207

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (6)

Details of each submission

From Athena Diagnostics, SCV001475136.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

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

From GeneDx, SCV005325897.1

#	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 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)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV005836645.1

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

Description

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.

#	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: Apr 13, 2025

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