ClinVar Genomic variation as it relates to human health
NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)
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.
Pathogenic(12); Likely pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001111.5(ADAR):c.577C>G (p.Pro193Ala)
Variation ID: 126395 Accession: VCV000126395.79
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.3 1: 154602065 (GRCh38) [ NCBI UCSC ] 1: 154574541 (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 Nov 10, 2024 Nov 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001111.5:c.577C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001102.3:p.Pro193Ala missense NM_001025107.3:c.-309C>G 5 prime UTR NM_001193495.2:c.-309C>G 5 prime UTR NM_001365045.1:c.604C>G NP_001351974.1:p.Pro202Ala missense NM_001365046.1:c.-309C>G 5 prime UTR NM_001365047.1:c.-309C>G 5 prime UTR NM_001365048.1:c.-309C>G 5 prime UTR NM_001365049.1:c.-309C>G 5 prime UTR NM_015840.4:c.577C>G NP_056655.3:p.Pro193Ala missense NM_015841.4:c.577C>G NP_056656.3:p.Pro193Ala missense NC_000001.11:g.154602065G>C NC_000001.10:g.154574541G>C NG_011844.2:g.34496C>G LRG_1212:g.34496C>G LRG_1212t1:c.577C>G LRG_1212p1:p.Pro193Ala P55265:p.Pro193Ala NP_001102.2:p.Pro193Ala - Protein change
- P193A, P202A
- Other names
- -
- Canonical SPDI
- NC_000001.11:154602064:G:C
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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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0.00140 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00162
Trans-Omics for Precision Medicine (TOPMed) 0.00244
1000 Genomes Project 0.00140
1000 Genomes Project 30x 0.00141
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00315
- Links
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 |
1247 | 1395 |
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 (10) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2023 | RCV000114336.33 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2024 | RCV000255775.46 | |
Pathogenic (3) |
criteria provided, single submitter
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May 28, 2019 | RCV000288094.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000352411.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 5, 2020 | RCV000624331.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000548694.22 | |
ADAR-related disorder
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2023 | RCV000778185.10 |
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
(Sep 08, 2017)
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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:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680137.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(May 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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ADAR-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914349.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ADAR c.577C>G (p.Pro193Ala) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in … (more)
The ADAR c.577C>G (p.Pro193Ala) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in at least 15 probands with ADAR-related disorders, including two sets of siblings and eight affected individuals from five families (Rice et al. 2012; Livingston et al. 2014; Schmelzer et al. 2018). The p.Pro193Ala variant has not been found in any affected individuals with dyschromatosis symmetrica hereditaria. Affected probands exhibited acute or subacute onset of striatal necrosis, early-onset encephalopathy, intracranial calcifications, developmental delay, severe and progressive dystonia, and often exhibited bilateral striatal necrosis (Rice et al. 2012; Livingston et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.003976 in the European population of the 1000 Genomes Project and observed in one homozygote in the Genome Aggregation Database. The p.Pro193Ala variant is reasonably common in the general population but still present at a frequency consistent with autosomal recessive disease. It is also noted that variants in the ADAR gene may have an atypical or milder presentation (Crow et al. 2016). Expression analysis of p.Pro193Ala in HEK293 cells showed a significant reduction in RNA-editing enzyme activity (Mannion et al. 2014). The loss of ADAR in hematopoietic stem cells in mice was associated with upregulation of type-I and type-II interferon-inducible transcripts and rapid apoptosis (Hartner et al. 2009). Based on the evidence, the p.Pro193Ala variant is classified as pathogenic for ADAR-Related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447200.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Developmental regression (present) , Abnormal corpus striatum morphology (present) , Hypotonia (present) , Orofacial dyskinesia (present)
Sex: male
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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: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003841227.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
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Pathogenic
(Mar 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742076.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.577C>G (p.P193A) alteration is located in coding exon 2 of the ADAR gene. This alteration results from a C to G substitution at nucleotide … (more)
The c.577C>G (p.P193A) alteration is located in coding exon 2 of the ADAR gene. This alteration results from a C to G substitution at nucleotide position 577, causing the proline (P) at amino acid position 193 to be replaced by an alanine (A). Based on the available evidence, the ADAR c.577C>G (p.P193A) alteration is classified as pathogenic for autosomal recessive Aicardi-Goutières syndrome; however, it is unlikely to be causative of autosomal dominant Aicardi-Goutières syndrome or dyschromatosis symmetrica hereditaria. Based on data from gnomAD, the G allele has an overall frequency of 0.21% (606/282848) total alleles studied. The highest observed frequency was 0.33% (426/129158) of European (non-Finnish) alleles. The ADAR c.577C>G (p.P193A) alteration is a recurrent Aicardi-Goutières syndrome (AGS)-associated alteration, which typically is found with a second null mutation (Crow, 2015; Rice, 2017). It has been reported in trans with other pathogenic ADAR variants in multiple unrelated individuals with AGS and ADAR-related disorders (Rice, 2012; Livingston, 2014; Rice, 2017; Schmelzer, 2018). This amino acid position is highly conserved in available vertebrate species. The p.P193 amino acid is located within the Z-DNA/Z-RNA binding domain. Structural modeling of the ADAR protein suggests that, in the wildtype protein, the p.P193 residue makes direct contact with the nucleic acid, and the p.P193A substitution removes important interactions between the ADAR protein and DNA/RNA (Rice, 2012). In one study, functional analysis in HEK293 cells demonstrated that the p.P193A alteration results in significantly decreased RNA-editing activity compared to wildtype (Mannion, 2014) while another study showed no significant effect on editing (Rice, 2012). Additionally, the P193A mutation, which is expressed only in the N-terminally extended ADAR1p150 isoform, was shown to increase the effect of other AGS mutations in the same protein (Mannion, 2014). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Feb 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Symmetrical dyschromatosis of extremities
Affected status: unknown
Allele origin:
paternal
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782783.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
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Pathogenic
(Dec 18, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000332712.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Likely pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Aicardi Goutieres syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711724.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Pro193Ala (NM_001111.4 c.577C>G) variant in ADAR has been reported in at l east 8 affected individuals (two of whom were identical twins) from 5 … (more)
The p.Pro193Ala (NM_001111.4 c.577C>G) variant in ADAR has been reported in at l east 8 affected individuals (two of whom were identical twins) from 5 families w ith Aicardi-Goutieres syndrome (Rice 2012) and 6 individuals from 5 families wit h bilateral striatal necrosis (Livingston 2014). All affected individuals were c ompound heterozygotes with a second ADAR variant. This variant has also been rep orted in ClinVar (Variation ID# 126395). The p.Pro193Ala variant has also been i dentified in 0.3% (199/66,740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145588689). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency (of note, the prevalence of the disease is unknown). Computational prediction tools and conservation analys is suggest that the p.Pro193Ala variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, althoug h additional studies are required to fully establish its clinical significance, the p.Pro193Ala variant is likely pathogenic based on its occurrence in individu als with this disease. (less)
Number of individuals with the variant: 2
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Symmetrical dyschromatosis of extremities
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135422.1
First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020 |
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Pathogenic
(Mar 06, 2019)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064425.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ADAR gene demonstrated a sequence change, c.577C>G, in exon 2 that results in an amino acid change, p.Pro193Ala. The p.Pro193Ala … (more)
DNA sequence analysis of the ADAR gene demonstrated a sequence change, c.577C>G, in exon 2 that results in an amino acid change, p.Pro193Ala. The p.Pro193Ala change affects a moderately conserved amino acid residue located in a domain of the ADAR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro193Ala substitution. The variant has been reported previously in the compound heterozygous state with another ADAR pathogenic variant in several individuals with Aicardi-Goutieres syndrome (Rice et al., 2012). Functional studies in HEK293 cells transfected with the p.Pro193Ala variant exhibit a significant decrease in RNA-editing enzyme activity (Mannion et al., 2014). This sequence change has been described in the gnomAD database with a population frequency of 0.21% (dbSNP rs145588689). We classify this sequence change as likely pathogenic. (less)
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Likely pathogenic
(-)
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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:
inherited
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Suma Genomics
Accession: SCV002097007.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Sep 01, 2022)
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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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3billion
Accession: SCV002572581.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.214%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.214%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.15). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000126395). The variant has been reported to be in trans with pathogenic variants as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28561207). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Motor delay (present) , Spasticity (present) , Tip-toe gait (present)
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Pathogenic
(Jul 11, 2023)
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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
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041618.2
First in ClinVar: Dec 25, 2021 Last updated: Aug 26, 2023 |
Comment:
Variant summary: ADAR c.577C>G (p.Pro193Ala) results in a non-conservative amino acid change located in the Z-binding domain (IPR042371) of the encoded protein sequence. Five of … (more)
Variant summary: ADAR c.577C>G (p.Pro193Ala) results in a non-conservative amino acid change located in the Z-binding domain (IPR042371) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 282848 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database, including one homozygote (of note, this homozygous carrier was also part of the non-neuro dataset of gnomAD v2.1). The observed relatively high frequency in non-Finnish Europeans, together with the homozygous occurrence, might indicate a benign nature for the variant. However, the variant, c.577C>G has also been reported in the literature in numerous compound heterozygous individuals, who were affected with phenotypes that belong to the Aicardi-Goutieres Syndrome 6 (AGS6) spectrum, including atypical (late-infantile and juvenile-onset) AGS, non-syndromic bilateral striatal necrosis (BSN), and calcifying cardiac valve disease (e.g. Rice_2012, Livingston_2014, Piekutowska-Abramczuk_2016, Kono_2018, Sathishkumar_2021, Crow_2020, Piccoli_2021). Of note, in several of these reported patients the signs of dyschromatosis symmetrica hereditaria (DSH) were also described (e.g. in Livingston_2014, Piekutowska-Abramczuk_2016, Kono_2018, Sathishkumar_2021, Crow_2020). In many patients, upregulation of IFN-stimulated genes (ISGs) were demonstrated, which is consistent with the proposed disease mechanism (e.g. Rice_2012, Livingston_2014). These data indicate that the variant is very likely to be associated with disease. A recent study noted that over 60% of AGS patients with ADAR mutations carry the P193A allele in compound heterozygous state with either a loss of function (LoF) mutation or a missense in the deaminase domain of ADAR1, however no homozygous patients have been reported (Maurano_2021). Authors of this study generated a knock-in mouse model for the variant, and found that P195A/P195A mice (P195A is homologous to human P193A) were indistinguishable from wild type controls, but compound heterozygous mice carrying the variant together with a more severe (i.e. null) ADAR allele, recapitulated the human AGS phenotype, with marked upregulation of ISGs (Maurano_2021); notably, homozygous null alleles of Adar in mice are known to result in embryonic lethality (OMIM). A publication also reported experimental evidence evaluating an impact on protein function, and demonstrated a partial loss of function for the variant protein (Mannion_2014). These data suggest that the pathogenicity of this variant is genotype-dependent, i.e. highly dependent on the variant observed in trans. The following publications have been ascertained in the context of this evaluation (PMID: 25456137, 28139822, 31772029, 29603717, 24262145, 34343497, 33307271, 23001123, 33289110, 33723056). 18 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments. Based on the evidence outlined above, the variant likely represents a hypomorphic allele that is subject to interallelic interactions, which in compound heterozygous state, together with other (more severe) variants in trans, can cause AGS6 and related phenotypes, therefore, this variant was classified as pathogenic. (less)
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Likely pathogenic
(Jul 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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ADAR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105363.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ADAR c.577C>G variant is predicted to result in the amino acid substitution p.Pro193Ala. This variant has been reported in the compound heterozygous state in … (more)
The ADAR c.577C>G variant is predicted to result in the amino acid substitution p.Pro193Ala. This variant has been reported in the compound heterozygous state in multiple families with Aicardi-Goutières syndrome and is predicted to disrupt DNA binding (Rice et al. 2012. PubMed ID: 23001123; Livingston et al. 2015. PubMed ID: 24262145; Piekutowska-Abramczuk et al. 2016. PubMed ID: 28139822). It was also reported in the compound heterozygous state in an individual who possibly had a mitochondrial disorder (Pronicka et al. 2016. PubMed ID: 27290639). Based on these observations, we interpret this variant as likely pathogenic. (less)
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Likely pathogenic
(Sep 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021311.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 31, 2024)
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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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000652396.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 193 of the ADAR protein (p.Pro193Ala). … (more)
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 193 of the ADAR protein (p.Pro193Ala). This variant is present in population databases (rs145588689, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive ADAR-related diseases (PMID: 23001123, 26629815). ClinVar contains an entry for this variant (Variation ID: 126395). 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. Experimental studies have shown that this missense change affects ADAR function (PMID: 9889202, 25456137, 34343497). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768143.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
A heterozygous missense variant was identified, NM_001111.5(ADAR):c.577C>G in exon 2 of 15 of the ADAR gene (NB: this variant is non-coding in alternative transcripts). This … (more)
A heterozygous missense variant was identified, NM_001111.5(ADAR):c.577C>G in exon 2 of 15 of the ADAR gene (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a minor amino acid change from a proline to an alanine at position 193 of the protein; NP_001102.3(ADAR):p.(Pro193Ala). The proline at this position has very high conservation (100 vertebrates, UCSC), and is located within the Z-DNA binding domain (Rice, G. I. et al. (2012)). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency at 0.21% (604 heterozygotes, 1 homozygote) and within the European sub-population frequency at 0.33%. This variant has been previously reported likely benign, likely pathogenic, pathogenic and VUS (ClinVar), but also as pathogenic in many patients with bilateral striatal necrosis or Aicardi-Goutieres syndrome (ClinVar, Piekutowska-Abramczuk, D. et al. (2016), Kono, M. et al. (2018)). It has also been shown to segregate with disease in several families (Rice, G. I. et al. (2012), Schmelzer, L. et al. (2018), Livingston, J. H. et al. (2014)). In addition, functional studies show that this variant causes reductions in RNA editing efficiency, but only in compound heterozygote with another pathogenic variant (Mannion, N. M. et al. (2014)). A different variant in the same codon resulting in a change to a serine has also been reported as a VUS (LOVD). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. (less)
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247918.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
ADAR: PM3:Strong, PM2, PM5, PS3:Moderate
Number of individuals with the variant: 6
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Pathogenic
(Nov 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321382.13
First in ClinVar: Oct 09, 2016 Last updated: Nov 10, 2024 |
Comment:
Conflicting evidence has been reported regarding the effect of this variant on protein function and structure (PMID: 25456137, 29603717); In silico analysis supports that this … (more)
Conflicting evidence has been reported regarding the effect of this variant on protein function and structure (PMID: 25456137, 29603717); 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: 33289110, 35960392, 37541188, 27539236, 29030706, 31692161, 24262145, 27290639, 28139822, 23001123, 29221912, 29603717, 30609409, 31664448, 31737037, 30729177, 31772029, 31980526, 34758253, 27943079, 34426522, 33307271, 34778129, 34631961, Liang[article]2022, 38292175, 35859177, 25456137, 37421629, 33528536) (less)
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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
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000244001.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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Pathogenic
(Feb 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: SCV000056412.5
First in ClinVar: Apr 04, 2013 Last updated: Apr 06, 2024 |
Comment on evidence:
In 5 families of European descent with Aicardi-Goutieres syndrome (AGS6; 615010), Rice et al. (2012) identified a heterozygous C-to-G transversion at nucleotide 577 in exon … (more)
In 5 families of European descent with Aicardi-Goutieres syndrome (AGS6; 615010), Rice et al. (2012) identified a heterozygous C-to-G transversion at nucleotide 577 in exon 2 of the ADAR gene, resulting in a pro-to-ala substitution at codon 193 (P193A). In 2 of these families, one Norwegian and the other Spanish, the mutation occurred in compound heterozygosity with an arg892-to-his mutation (146920.0008). The other 3 families respectively carried the P193A mutation in compound heterozygosity with A870T (146920.0009), I872T (146920.0014), and a 5-bp deletion (146920.0015). Proline-293 is highly evolutionarily conserved and positioned within the Z-DNA/Z-RNA-binding domain. This variant was also observed in 41 subjects (32 of 4,350 European Americans and 9 of 2,203 African Americans) in the Exome Variant Server database. In 6 patients, including 2 sibs, with atypical AGS6, Livingston et al. (2014) identified the P193A mutation in compound heterozygosity with another pathogenic ARAR mutation (see, e.g., I872T and R544XC, 146920.0016). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Aicardi-Goutieres syndrome 6
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001759988.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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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
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GeneReviews
Accession: SCV000147906.3
First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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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:
unknown,
maternal
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GenomeConnect - Brain Gene Registry
Accession: SCV003931214.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant classified as Likely pathogenic and reported most recently on 09-09-2022 by PerkinElmer Genomics … (more)
Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant classified as Likely pathogenic and reported most recently on 09-09-2022 by PerkinElmer Genomics and as Uncertain significance on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Observation 1:
Clinical Features:
Short stature (present) , Attention deficit hyperactivity disorder (present) , Intellectual disability, borderline (present) , Global developmental delay (present) , Memory impairment (present) , Specific … (more)
Short stature (present) , Attention deficit hyperactivity disorder (present) , Intellectual disability, borderline (present) , Global developmental delay (present) , Memory impairment (present) , Specific learning disability (present) , Seizure (present) , Status epilepticus without prominent motor symptoms (present) , Abnormal facial shape (present) , Astigmatism (present) , Polymorphous corneal dystrophy (present) , Amblyopia (present) , Hypomimic face (present) , Gait disturbance (present) , Hip contracture (present) , Limited hip extension (present) , Bilateral coxa valga (present) , Hyperlordosis (present) , Muscle weakness (present) , Muscle stiffness (present) , Lower limb asymmetry (present) , Gynecomastia (present) , Alopecia (present) , Decreased body weight (present) , Downslanted palpebral fissures (present) , Micrognathia (present) , Protruding ear (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Exome Sequencing
Testing laboratory: Revvity Omics, Revvity
Date variant was reported to submitter: 2022-09-09
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Clinical Features:
Recurrent streptococcal infections (present) , Delayed speech and language development (present) , Intellectual disability (present) , Abnormal facial shape (present)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Exome Sequencing
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-02-03
Testing laboratory interpretation: Uncertain significance
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Uncertain significance
(May 30, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Symmetrical dyschromatosis of extremities
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001527725.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Jan 01, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Symmetrical dyschromatosis of extremities
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440574.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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ADAR1 mutation causes ZBP1-dependent immunopathology. | Hubbard NW | Nature | 2022 | PMID: 35859177 |
Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1. | Maurano M | Immunity | 2021 | PMID: 34343497 |
Decoupling expression and editing preferences of ADAR1 p150 and p110 isoforms. | Sun T | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 33723056 |
Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features. | Piccoli C | Pediatric neurology | 2021 | PMID: 33307271 |
Co-occurrence of Aicardi-Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1: a case series from India. | Sathishkumar D | Clinical and experimental dermatology | 2021 | PMID: 33289110 |
Cardiac valve involvement in ADAR-related type I interferonopathy. | Crow Y | Journal of medical genetics | 2020 | PMID: 31772029 |
Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression. | Kono M | The British journal of dermatology | 2018 | PMID: 29603717 |
Variable clinical phenotype in two siblings with Aicardi-Goutières syndrome type 6 and a novel mutation in the ADAR gene. | Schmelzer L | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2018 | PMID: 29221912 |
Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease. | Rice GI | Neuropediatrics | 2017 | PMID: 28561207 |
Bilateral striatal necrosis caused by ADAR mutations in two siblings with dystonia and freckles-like skin changes that should be differentiated from Leigh syndrome. | Piekutowska-Abramczuk D | Folia neuropathologica | 2016 | PMID: 28139822 |
Aicardi-Goutières Syndrome. | Adam MP | - | 2016 | PMID: 20301648 |
ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells. | Cuadrado E | PloS one | 2015 | PMID: 26629815 |
Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. | Crow YJ | American journal of medical genetics. Part A | 2015 | PMID: 25604658 |
The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. | Mannion NM | Cell reports | 2014 | PMID: 25456137 |
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 |
ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. | Hartner JC | Nature immunology | 2009 | PMID: 19060901 |
Structure-function analysis of the Z-DNA-binding domain Zalpha of dsRNA adenosine deaminase type I reveals similarity to the (alpha + beta) family of helix-turn-helix proteins. | Schade M | The EMBO journal | 1999 | PMID: 9889202 |
http://web.expasy.org/variant_pages/VAR_069535.html | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ADAR | - | - | - | - |
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Text-mined citations for rs145588689 ...
HelpRecord last updated Nov 25, 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.