ClinVar Genomic variation as it relates to human health
NM_001111.5(ADAR):c.3019G>A (p.Gly1007Arg)
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_001111.5(ADAR):c.3019G>A (p.Gly1007Arg)
Variation ID: 39458 Accession: VCV000039458.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.3 1: 154588125 (GRCh38) [ NCBI UCSC ] 1: 154560601 (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 Mar 24, 2015 Oct 8, 2024 Jun 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001111.5:c.3019G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001102.3:p.Gly1007Arg missense NM_001025107.3:c.2134G>A NP_001020278.1:p.Gly712Arg missense NM_001193495.2:c.2134G>A NP_001180424.1:p.Gly712Arg missense NM_001365045.1:c.3046G>A NP_001351974.1:p.Gly1016Arg missense NM_001365046.1:c.2134G>A NP_001351975.1:p.Gly712Arg missense NM_001365047.1:c.2134G>A NP_001351976.1:p.Gly712Arg missense NM_001365048.1:c.2134G>A NP_001351977.1:p.Gly712Arg missense NM_001365049.1:c.2056G>A NP_001351978.1:p.Gly686Arg missense NM_015840.4:c.2941G>A NP_056655.3:p.Gly981Arg missense NM_015841.4:c.2884G>A NP_056656.3:p.Gly962Arg missense NC_000001.11:g.154588125C>T NC_000001.10:g.154560601C>T NG_011844.2:g.48436G>A LRG_1212:g.48436G>A LRG_1212t1:c.3019G>A LRG_1212p1:p.Gly1007Arg NP_001102.2:p.Gly1007Arg - Protein change
- G1007R, G712R, G981R, G1016R, G962R, G686R
- Other names
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- Canonical SPDI
- NC_000001.11:154588124:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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ADAR | - | - |
GRCh38 GRCh37 |
1239 | 1386 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2024 | RCV000032654.48 | |
Likely pathogenic (2) |
criteria provided, single submitter
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May 14, 2013 | RCV000032653.33 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 13, 2023 | RCV000762850.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001091722.24 |
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
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001805453.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in published literature in multiple affected individuals from a few unrelated families with dyschromatosis symmetrica hereditaria and neurodegeneration with dystonia and intracranial calcification. Also … (more)
Reported in published literature in multiple affected individuals from a few unrelated families with dyschromatosis symmetrica hereditaria and neurodegeneration with dystonia and intracranial calcification. Also present in multiple unaffected relatives in these families, suggesting G1007R may exhibit incomplete penetrance (Suzuki et al., 2005; Kondo et al., 2008); Published functional studies suggest that G1007R may confer a dominant-negative effect by binding more tightly to RNA and acting as competitive inhibitor to the wild-type protein (Rice et al., 2012); Not observed at significant frequency 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: 29775506, 24262145, 25243380, 19017046, 16817193, 27959697, 15955093, 23001123, 29691679, 31737037, 34426522, 32801363, 33307271, 27535533) (less)
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Pathogenic
(May 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001430630.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
This ADAR variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in at least eleven individuals … (more)
This ADAR variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in at least eleven individuals from nine families with autosomal dominant Aicardi-Goutieres syndrome. In four families, the c.3019G>A variant occurred de novo. Independent functional studies have shown that the p.Gly1007Arg substitution inhibits the RNA editing activity of ADAR1, presumably through steric hindrance at the base-flipping step of the deaminase reaction. We consider this variant to be pathogenic. (less)
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Pathogenic
(Jun 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005061416.1
First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024 |
Comment:
heterozygous
Clinical Features:
Polyneuropathy (present) , Gait disturbance (present) , Muscle weakness (present) , Hyperreflexia (present) , Dysphonia (present) , Paraparesis (present) , Expressive language delay (present) , … (more)
Polyneuropathy (present) , Gait disturbance (present) , Muscle weakness (present) , Hyperreflexia (present) , Dysphonia (present) , Paraparesis (present) , Expressive language delay (present) , Decreased circulating vitamin D concentration (present) (less)
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Pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Symmetrical dyschromatosis of extremities
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002237768.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change affects ADAR function (PMID: 26802932, 29775506). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39458). This missense change has been observed in individual(s) with clinical features of autosomal dominant dyschromatosis symmetrica hereditaria and/or autosomal dominant Aicardi Goutieres syndrome (PMID: 15955093, 16817193, 19017046, 23001123, 24262145, 25243380, 28561207, 29691679, 32801363, 33307271). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1007 of the ADAR protein (p.Gly1007Arg). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. (less)
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Pathogenic
(Jul 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000328705.2
First in ClinVar: Feb 02, 2016 Last updated: Mar 11, 2023 |
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Pathogenic
(Sep 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764954.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Epicanthus (present) , Intellectual disability (present) , Low-set ears (present) , Dystonic disorder (present) , Cerebral hypomyelination (present) , Global developmental delay (present) , Clinodactyly … (more)
Epicanthus (present) , Intellectual disability (present) , Low-set ears (present) , Dystonic disorder (present) , Cerebral hypomyelination (present) , Global developmental delay (present) , Clinodactyly of the 4th toe (present) , Microcephaly (present) , Short stature (present) (less)
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Likely pathogenic
(May 14, 2013)
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criteria provided, single submitter
Method: clinical testing
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Symmetrical dyschromatosis of extremities
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255319.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hispanic
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(Mar 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368860.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073235.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.G1007R in ADAR (NM_001111.5) has been previously reported in multiple individuals with dominant Aicardi Goutieres syndrome (Kondo T et al,2008). Functional analysis … (more)
The missense variant p.G1007R in ADAR (NM_001111.5) has been previously reported in multiple individuals with dominant Aicardi Goutieres syndrome (Kondo T et al,2008). Functional analysis revealed a damagig effect (Fisher AJ et al,2017). The variant has been submitted to ClinVar as Pathogenic. The p.G1007R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1007R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3019 in ADAR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Systemic lupus erythematosus (present) , Antiphospholipid antibody positivity (present) , Abnormal facial shape (present) , Fever (present) , Body ache (present) , Atrophy of the … (more)
Systemic lupus erythematosus (present) , Antiphospholipid antibody positivity (present) , Abnormal facial shape (present) , Fever (present) , Body ache (present) , Atrophy of the spinal cord (present) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
unknown
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Wangler Lab, Baylor College of Medicine
Accession: SCV002587798.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Comment:
This ADAR variant at c.3019G>A (p.G1007R) was seen on exome through the Texome project (R01HG011795). This variant has been described as a de novo variant … (more)
This ADAR variant at c.3019G>A (p.G1007R) was seen on exome through the Texome project (R01HG011795). This variant has been described as a de novo variant in the heterozygous state in individuals with autosomal dominant Aicardi-Goutières syndrome (PMID: 23001123, 33307271) and in individuals with dyschromatosis symmetrica hereditaria with additional features including dystonia, mental deterioration and brain MRI abnormalities (PMID: 16817193, 19017046). In addition, this heterozygous variant has been described in two individuals with tremors, spasticity/dystonia, abnormal MRI findings and progressive motor deterioration (PMID: 24262145, 29691679) and two internal cases with a similar phenotype. This variant is absent from gnomAD (PM2). Functional studies suggest this variant showed a significant effect on editing function of the protein, with levels of editing equivalent to those seen with inactive protein (PMID: 23001123) (PS3). This heterozygous variant shows RNA editing deficiency similar to Aicardi-Goutières associated variants and more severely affected when compared to dyschromatosis symmetrica hereditaria associated variants (PMID: 26802932).This variant lies at the last nucleotide of exon 11 (of 15) for the reported transcript. This variant is predicted to be deleterious(CADD: 34.000, SpliceAI: 0.190) (PP3). The evolutionary conservation of this residue is high. Variant is located in the adenosinede aminase/editase domain (PMID: 23001123). We classify this variant as pathogenic. (less)
Age: 0-9 years
Sex: female
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004050328.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247915.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Comment:
ADAR: PS2, PM2, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Accession: SCV005050191.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
The NM_001111.5: c.3019G>A variant is located in exon 11 of the ADAR gene. This variant involves a change at the protein level from Glycine to … (more)
The NM_001111.5: c.3019G>A variant is located in exon 11 of the ADAR gene. This variant involves a change at the protein level from Glycine to Arginine at position 1007 (p.(Gly1007Arg)). This position is highly conserved and corresponds to a well-established domain of the protein. This variant has a null frequency in population databases and, in turn, has numerous reports in ClinVar, where it is classified as likely pathogenic/pathogenic (ClinVarID: 39458). In addition, more than 4 cases have been reported in which the variant was found 'de novo' (PMID: 23001123, 33307271). On the other hand, bioinformatic tools predict that the variant would be deleterious, which agrees with what has been demonstrated through functional studies (PMID: 25243380, 26372505). It is important to highlight that, although patients with the AGS phenotype associated with an autosomal recessive inheritance pattern have been described, this particular variant behaves as dominant-negative, so affected patients are heterozygous for said variant. (PS3supporting, PM1supporting, PM2moderate, PM6strong, PP3moderate) (less)
Clinical Features:
Psychomotor deterioration (present) , Spasticity (present) , Leukodystrophy (present) , Leukodystrophy (present) , Microcephaly (present)
Age: 10-19 years
Sex: female
Geographic origin: Argentina
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Likely pathogenic
(Jun 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Symmetrical dyschromatosis of extremities
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
germline
|
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust
Accession: SCV004814241.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
Criteria Codes: PS3 PS4_Mod PM2 PP3
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Symmetrical dyschromatosis of extremities
Aicardi-Goutieres syndrome 6
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893210.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jun 27, 2013)
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no assertion criteria provided
Method: literature only
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Aicardi-goutieres syndrome 6
Affected status: yes
Allele origin:
germline
|
ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000244028.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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Pathogenic
(Dec 01, 2014)
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no assertion criteria provided
Method: literature only
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DYSCHROMATOSIS SYMMETRICA HEREDITARIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056416.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2024 |
Comment on evidence:
Dyschromatosis Symmetrica Hereditaria In a 22-year-old Japanese woman with dyschromatosis symmetrica hereditaria (DSH; 127400) associated with dystonia, mental deterioration, and tissue calcification, Tojo et al. … (more)
Dyschromatosis Symmetrica Hereditaria In a 22-year-old Japanese woman with dyschromatosis symmetrica hereditaria (DSH; 127400) associated with dystonia, mental deterioration, and tissue calcification, Tojo et al. (2006) identified heterozygosity for a c.3019G-A transition in exon 11 of the ADAR gene, resulting in a gly1007-to-arg (G1007R) substitution. Her unaffected mother and sister did not carry the mutation; DNA was unavailable from her affected deceased father. In an 11-year-old Japanese boy with DSH and dystonia, mental deterioration, and brain calcification, Kondo et al. (2008) identified heterozygosity for the previously reported G1007R substitution in the ADAR gene. His mother, who had skin lesions but no neurologic features, was also heterozygous for the mutation. Aicardi-Goutieres Syndrome In 2 individuals, 1 of Brazilian origin and 1 of European American origin, with Aicardi-Goutieres syndrome-6 (AGS6; 615010), Rice et al. (2012) identified a heterozygous de novo mutation in exon 11 of the ADAR gene: a G-to-A transition at nucleotide 3019, resulting in a gly-to-arg substitution at codon 1007 (G1007R). Using an ADAR1 editing substrate, miR376-a2 (610960), Rice et al. (2012) found that, of 6 ADAR mutations tested, only the G1007R variant showed a significant effect on editing, with levels of editing equivalent to those seen with inactive protein. The proximity of G1007R to the RNA backbone and the possibility for an arginine residue to make polymorphic interactions there suggested a mechanism whereby arg1007 might confer a dominant-negative effect: by binding more tightly to RNA the mutant protein could act as a competitive inhibitor of wildtype protein while being itself catalytically inactive. Rice et al. (2012) found that a plasmid expressing G1007R ADAR1 showed stronger inhibition of wildtype ADAR1 than equivalent amounts of a plasmid expressing catalytically inactive ADAR1. In 2 half-sibs with AGS6, Livingston et al. (2014) found the G1007R mutation in heterozygosity. In a 5-year-old boy, born of unrelated Hispanic parents, with onset of nonsyndromic spastic paraplegia at age 2 years following normal psychomotor development, Crow et al. (2014) identified a de novo heterozygous G1007R mutation in the ADAR1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Brain imaging and cognition were normal, and laboratory studies showed increased interferon. Crow et al. (2014) emphasized the emerging phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder. (less)
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Pathogenic
(Dec 01, 2014)
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no assertion criteria provided
Method: literature only
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AICARDI-GOUTIERES SYNDROME 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056417.8
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2024 |
Comment on evidence:
Dyschromatosis Symmetrica Hereditaria In a 22-year-old Japanese woman with dyschromatosis symmetrica hereditaria (DSH; 127400) associated with dystonia, mental deterioration, and tissue calcification, Tojo et al. … (more)
Dyschromatosis Symmetrica Hereditaria In a 22-year-old Japanese woman with dyschromatosis symmetrica hereditaria (DSH; 127400) associated with dystonia, mental deterioration, and tissue calcification, Tojo et al. (2006) identified heterozygosity for a c.3019G-A transition in exon 11 of the ADAR gene, resulting in a gly1007-to-arg (G1007R) substitution. Her unaffected mother and sister did not carry the mutation; DNA was unavailable from her affected deceased father. In an 11-year-old Japanese boy with DSH and dystonia, mental deterioration, and brain calcification, Kondo et al. (2008) identified heterozygosity for the previously reported G1007R substitution in the ADAR gene. His mother, who had skin lesions but no neurologic features, was also heterozygous for the mutation. Aicardi-Goutieres Syndrome In 2 individuals, 1 of Brazilian origin and 1 of European American origin, with Aicardi-Goutieres syndrome-6 (AGS6; 615010), Rice et al. (2012) identified a heterozygous de novo mutation in exon 11 of the ADAR gene: a G-to-A transition at nucleotide 3019, resulting in a gly-to-arg substitution at codon 1007 (G1007R). Using an ADAR1 editing substrate, miR376-a2 (610960), Rice et al. (2012) found that, of 6 ADAR mutations tested, only the G1007R variant showed a significant effect on editing, with levels of editing equivalent to those seen with inactive protein. The proximity of G1007R to the RNA backbone and the possibility for an arginine residue to make polymorphic interactions there suggested a mechanism whereby arg1007 might confer a dominant-negative effect: by binding more tightly to RNA the mutant protein could act as a competitive inhibitor of wildtype protein while being itself catalytically inactive. Rice et al. (2012) found that a plasmid expressing G1007R ADAR1 showed stronger inhibition of wildtype ADAR1 than equivalent amounts of a plasmid expressing catalytically inactive ADAR1. In 2 half-sibs with AGS6, Livingston et al. (2014) found the G1007R mutation in heterozygosity. In a 5-year-old boy, born of unrelated Hispanic parents, with onset of nonsyndromic spastic paraplegia at age 2 years following normal psychomotor development, Crow et al. (2014) identified a de novo heterozygous G1007R mutation in the ADAR1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Brain imaging and cognition were normal, and laboratory studies showed increased interferon. Crow et al. (2014) emphasized the emerging phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000147905.3
First in ClinVar: Apr 27, 2014 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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Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy. | Jones HF | Brain & development | 2022 | PMID: 34702576 |
Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features. | Piccoli C | Pediatric neurology | 2021 | PMID: 33307271 |
When phenotype does not match genotype: importance of "real-time" refining of phenotypic information for exome data interpretation. | Basel-Salmon L | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32801363 |
Dyschromatosis symmetrica hereditaria with chilblains due to a novel two-amino-acid deletion in the double-stranded RNA-binding domain of ADAR1. | Kono M | Journal of the European Academy of Dermatology and Venereology : JEADV | 2018 | PMID: 29775506 |
The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. | Travaglini L | Neurogenetics | 2018 | PMID: 29691679 |
Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease. | Rice GI | Neuropediatrics | 2017 | PMID: 28561207 |
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures. | Fisher AJ | RNA biology | 2017 | PMID: 27937139 |
Genetic spectrum of dyschromatosis symmetrica hereditaria in Chinese patients including a novel nonstop mutation in ADAR1 gene. | Zhang G | BMC medical genetics | 2016 | PMID: 26892242 |
Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations. | Kono M | The Journal of investigative dermatology | 2016 | PMID: 26802932 |
Aicardi-Goutières Syndrome. | Adam MP | - | 2016 | PMID: 20301648 |
A Phenotypic Screen for Functional Mutants of Human Adenosine Deaminase Acting on RNA 1. | Wang Y | ACS chemical biology | 2015 | PMID: 26372505 |
Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. | Crow YJ | Neuropediatrics | 2014 | PMID: 25243380 |
A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. | Livingston JH | Journal of medical genetics | 2014 | PMID: 24262145 |
Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. | Rice GI | Nature genetics | 2012 | PMID: 23001123 |
Dyschromatosis symmetrica hereditaria associated with neurological disorders. | Kondo T | The Journal of dermatology | 2008 | PMID: 19017046 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. | Tojo K | Movement disorders : official journal of the Movement Disorder Society | 2006 | PMID: 16817193 |
Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis. | Suzuki N | The Journal of investigative dermatology | 2005 | PMID: 15955093 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://web.expasy.org/variant_pages/VAR_069540.html | - | - | - | - |
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HelpRecord last updated Oct 08, 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.