ClinVar Genomic variation as it relates to human health
NM_002055.5(GFAP):c.1246C>T (p.Arg416Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002055.5(GFAP):c.1246C>T (p.Arg416Trp)
Variation ID: 16169 Accession: VCV000016169.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44908075 (GRCh38) [ NCBI UCSC ] 17: 42985443 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 19, 2013 Feb 14, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002055.5:c.1246C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002046.1:p.Arg416Trp missense NM_001363846.2:c.1366C>T NP_001350775.1:p.Arg456Trp missense NC_000017.11:g.44908075G>A NC_000017.10:g.42985443G>A NG_008401.1:g.12472C>T P14136:p.Arg416Trp - Protein change
- R416W, R456W
- Other names
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- Canonical SPDI
- NC_000017.11:44908074:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GFAP | - | - |
GRCh38 GRCh37 |
441 | 510 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2022 | RCV000017552.49 | |
Pathogenic (2) |
criteria provided, single submitter
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Jul 17, 2023 | RCV000056848.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 6, 2019 | RCV001267511.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alexander disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767965.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Fuctional studies have demonstrated both dominant negative and gain of function are possible mechanisms of disease, where the latter is the more widely accepted mechanism (OMIM, GeneReviews, PMID: 11138011, PMID: 30355500, PMID: 31484723). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated tail domain (PMID: 31611638). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and shown to be de novo in a patient with Alexander disease (ClinVar). It has also been reported in multiple other patients with infantile-, juvenile- and adult-onset Alexander disease, both familial and sporadic (PMID: 31611638, PMID: 18684770, PMID: 27814755). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alexander disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680243.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Pathogenic
(Nov 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445692.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the periventricular white matter (present) , Abnormal brainstem MRI signal intensity (present) , Abnormality of the spinal cord (present) , Generalized tonic-clonic seizures … (more)
Abnormality of the periventricular white matter (present) , Abnormal brainstem MRI signal intensity (present) , Abnormality of the spinal cord (present) , Generalized tonic-clonic seizures (present) , EEG abnormality (present) , Optic atrophy (present) , Optic disc pallor (present) , Ptosis (present) , Nystagmus (present) , Opsoclonus (present) , Lethargy (present) , Fatigue (present) , Hemiparesis (present) , Exercise intolerance (present) , Hyperreflexia (present) , Clonus (present) , Muscle weakness (present) , Failure to thrive (present) , Poor appetite (present) , Episodic vomiting (present) , Gastroesophageal reflux (present) , Anxiety (present) , Abnormality of thyroid morphology (present) , Bicuspid aortic valve (present) , Aortic root dilatation (present) , Cafe-au-lait spot (present) , Nevus (present) , Sleep disturbance (present) , Vitamin D deficiency (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Nov 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alexander disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818146.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002246484.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the GFAP protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the GFAP protein (p.Arg416Trp). This variant is present in population databases (rs121909717, gnomAD 0.01%). This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 27814755). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16169). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. Experimental studies have shown that this missense change affects GFAP function (PMID: 16826512). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2006)
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no assertion criteria provided
Method: literature only
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ALEXANDER DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037824.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 19, 2019 |
Comment on evidence:
In 2 unrelated patients with Alexander disease (ALXDRD; 203450) that led to death at ages 7 and 8, respectively, Brenner et al. (2001) identified a … (more)
In 2 unrelated patients with Alexander disease (ALXDRD; 203450) that led to death at ages 7 and 8, respectively, Brenner et al. (2001) identified a C-to-T transition at nucleotide 1260 of the GFAP gene, resulting in an arg416-to-trp substitution. Li et al. (2005) noted that the R416W mutation had been identified in patients with infantile-, juvenile-, and adult-onset Alexander disease. A pathologic hallmark of Alexander disease is the abundance of protein aggregates in astrocytes. These aggregates, termed Rosenthal fibers, contain the protein chaperones alpha-B crystallin (123590) and HSP27 (602195) as well as GFAP. Der Perng et al. (2006) showed that the R416W mutation in GFAP significantly perturbs in vitro filament assembly. The filamentous structures formed resemble assembly intermediates but aggregated more strongly. Consistent with the heterozygosity of the mutation, this effect was dominant over wildtype GFAP in coassembly experiments. Transient transfection studies demonstrated that R416W GFAP induces the formation of GFAP-containing cytoplasmic aggregates in a wide range of different cell types, including astrocytes. Monoclonal antibodies specific for R146W GFAP revealed, for the first time for any intermediate filament-based disease, the presence of the mutant protein in the characteristic histopathologic features of the disease, namely, Rosenthal fibers. The data confirmed that the effects of the R416W GFAP are dominant, changing the assembly process in a way that encourages aberrant filament-filament interactions that then lead to protein aggregation and chaperone sequestration as early events in Alexander disease. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000087961.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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not provided
(-)
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no classification provided
Method: literature only
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Alexander disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000223052.3
First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Alexander Disease. | Adam MP | - | 2020 | PMID: 20301351 |
Towards genomic database of Alexander disease to identify variations modifying disease phenotype. | Yasuda R | Scientific reports | 2019 | PMID: 31611638 |
Relative stabilities of wild-type and mutant glial fibrillary acidic protein in patients with Alexander disease. | Heaven MR | The Journal of biological chemistry | 2019 | PMID: 31484723 |
Aggregate formation analysis of GFAP(R416W) found in one case of Alexander disease. | Tulyeu J | Brain & development | 2019 | PMID: 30213442 |
Mutations in GFAP Disrupt the Distribution and Function of Organelles in Human Astrocytes. | Jones JR | Cell reports | 2018 | PMID: 30355500 |
Atypical MRI features in familial adult onset Alexander disease: case report. | Liu Y | BMC neurology | 2016 | PMID: 27814755 |
Diagnosis by whole exome sequencing of atypical infantile onset Alexander disease masquerading as a mitochondrial disorder. | Nishri D | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2014 | PMID: 24742911 |
Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. | Pareyson D | Brain : a journal of neurology | 2008 | PMID: 18684770 |
Can MR imaging diagnose adult-onset Alexander disease? | Farina L | AJNR. American journal of neuroradiology | 2008 | PMID: 18388212 |
GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease. | Caroli F | Clinical genetics | 2007 | PMID: 17894839 |
The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. | Der Perng M | American journal of human genetics | 2006 | PMID: 16826512 |
Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. | van der Knaap MS | Neurology | 2006 | PMID: 16505300 |
Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. | Li R | Annals of neurology | 2005 | PMID: 15732097 |
Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. | Thyagarajan D | Movement disorders : official journal of the Movement Disorder Society | 2004 | PMID: 15390001 |
A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation. | Kinoshita T | Neuroscience letters | 2003 | PMID: 14550921 |
Molecular findings in symptomatic and pre-symptomatic Alexander disease patients. | Gorospe JR | Neurology | 2002 | PMID: 12034785 |
Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. | Brenner M | Nature genetics | 2001 | PMID: 11138011 |
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Text-mined citations for rs121909717 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.