ClinVar Genomic variation as it relates to human health
NM_001282225.2(ADA2):c.139G>A (p.Gly47Arg)
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_001282225.2(ADA2):c.139G>A (p.Gly47Arg)
Variation ID: 120304 Accession: VCV000120304.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q11.1 22: 17209539 (GRCh38) [ NCBI UCSC ] 22: 17690429 (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 11, 2015 Apr 15, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001282225.2:c.139G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001269154.1:p.Gly47Arg missense NM_001282225.1:c.[139G>A] NM_001282226.2:c.139G>A NP_001269155.1:p.Gly47Arg missense NM_001282227.2:c.13G>A NP_001269156.1:p.Gly5Arg missense NM_001282228.2:c.13G>A NP_001269157.1:p.Gly5Arg missense NM_001282229.2:c.-38-2249G>A intron variant NC_000022.11:g.17209539C>T NC_000022.10:g.17690429C>T NG_033943.1:g.17316G>A LRG_1217:g.17316G>A LRG_1217t1:c.139G>A LRG_1217p1:p.Gly47Arg - Protein change
- G47R, G5R
- Other names
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- Canonical SPDI
- NC_000022.11:17209538: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00010
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
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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
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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ADA2 | - | - |
GRCh38 GRCh37 |
502 | 580 |
Conditions - Germline
Condition
Help
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
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 (11) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000106385.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001091906.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 26, 2021 | RCV002262705.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2021 | RCV002498474.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003445509.2 |
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
(Mar 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV000992340.1
First in ClinVar: Sep 12, 2019 Last updated: Sep 12, 2019 |
Comment:
This ADA2 variant (rs202134424) has been reported to segregate with disease in multiple unrelated families with ADA2-deficiency. It is rare (> or = 0.1%) in … (more)
This ADA2 variant (rs202134424) has been reported to segregate with disease in multiple unrelated families with ADA2-deficiency. It is rare (> or = 0.1%) in large population datasets (gnomAD: 30/282718 total alleles; 0.01%; no homozygotes). Two submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant is located within the dimerization domain of ADA2 and is thought to affect the stability of homodimers or their individual subunits. Functional studies have shown that levels of ADA2 in multiple cell types were significantly lower in mutant proteins compared to non-mutant proteins, supporting the pathogenicity of this variant. Multiple alternate pathogenic missense variants have been reported within the same residue (p.Gly47Ala; p.Gly47Val). ADA2 c.139G>A is considered pathogenic. (less)
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Pathogenic
(Mar 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001547502.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Family history: no
Sex: female
Secondary finding: no
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073342.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.G47R in ADA2 (NM_001282225.2) causes the same amino acid change as a previously established pathogenic variant. This variant has been observed to … (more)
The missense variant p.G47R in ADA2 (NM_001282225.2) causes the same amino acid change as a previously established pathogenic variant. This variant has been observed to segregate with ADA2 deficiency and polyarteritis nodosa in several families (Navon Elkan et al, 2014; Poswar Fde et al, 2016; Nanthapisal S et al, 2016; Skrabl-Baumgartner A et al, 2017). The p.G47R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 47 of ADA2 is conserved in all mammalian species. The nucleotide c.139 in ADA2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies studies have shown that this missense change leads to defective ADA2 activity (Navon Elkan et al, 2014). For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Vasculitis (present) , Genital ulcers (present) , Hyperpigmentation of the skin (present) , Recurrent cerebral hemorrhage (present) , Diplopia (present) , Hearing impairment (present)
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Pathogenic
(Feb 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002099533.1
First in ClinVar: Mar 03, 2022 Last updated: Mar 03, 2022 |
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Pathogenic
(Nov 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543370.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Likely pathogenic
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784564.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Pathogenic
(Dec 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sneddon syndrome
Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811609.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Sneddon syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171922.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000941825.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the ADA2 protein (p.Gly47Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the ADA2 protein (p.Gly47Arg). This variant is present in population databases (rs202134424, gnomAD 0.07%). This missense change has been observed in individuals with ADA2 deficiency and polyarteritis nodosa (PMID: 24552284, 24552285, 25075844, 25278816, 26914925, 27059682, 28522451, 28830446). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 120304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADA2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24552284, 24552285, 28493328, 28522451, 29391272). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803992.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: CECR1 (ADA2) c.139G>A (p.Gly47Arg) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase N-terminal domain (IPR013659) of the encoded protein … (more)
Variant summary: CECR1 (ADA2) c.139G>A (p.Gly47Arg) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase N-terminal domain (IPR013659) 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 0.00011 in 251330 control chromosomes (gnomAD). c.139G>A has been reported in the literature in multiple individuals affected with ADA2 Deficiency/Polyarteritis Nodosa, primarily with a childhood onset and has been found to segregate with disease in several families (e.g. Navon Elkan_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found that variant effect results in <10% of normal activity (Jee_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34004258, 24552285). ClinVar contains an entry for this variant (Variation ID: 120304). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807021.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141328.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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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: SCV001248185.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ADA2: PS1, PM1, PM2, PM3, PM5, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Mar 06, 2014)
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no assertion criteria provided
Method: literature only
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VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000143889.5
First in ClinVar: Apr 01, 2014 Last updated: May 10, 2021 |
Comment on evidence:
In 3 Turkish patients, including 2 sibs, with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified a homozygous c.139G-A … (more)
In 3 Turkish patients, including 2 sibs, with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified a homozygous c.139G-A transition in exon 2 of the CECR1 gene, resulting in a gly47-to-arg (G47R) substitution at a highly conserved residue in the dimerization domain. Haplotype analysis indicated a founder effect, and the carrier frequency of this variant in Turkish controls was 0.002. The G47R mutation was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ClinSeq 801 databases. Navon Elkan et al. (2014) identified a homozygous G47R mutation in 19 Georgian Jewish individuals with polyarteritis nodosa. Sixteen of the patients were from 5 multiplex families, and 3 patients had apparently sporadic disease. Fifteen of the patients were diagnosed before 10 years of age, including 6 in infancy. In contrast, 1 patient had onset of the disorder with leg ulcers at age 59 years. The mutation, which was found by exome sequencing in the initial patients and later found and confirmed by Sanger sequencing in the other patients, was not present in 864 in-house exomes or in more than 7,500 exome sequences present in public databases. Among 246 unrelated Georgian Jewish controls, 25 were heterozygous for the mutation, yielding a carrier frequency of 0.102 in this population. Serum ADA2 activity in homozygous mutation carriers was reduced by a factor of more than 4 compared to controls. Transfection of the mutation into Drosophila cells resulted in decreased expression of the mutant protein compared to wildtype. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Vasculitis due to ADA2 deficiency
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000994596.2
First in ClinVar: Oct 01, 2019 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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Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach. | Jee H | The Journal of allergy and clinical immunology | 2022 | PMID: 34004258 |
Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. | Meyts I | Journal of clinical immunology | 2018 | PMID: 29951947 |
Identification of co-occurrence in a patient with Dent's disease and ADA2-deficiency by exome sequencing. | Günthner R | Gene | 2018 | PMID: 29391272 |
Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders. | Hashem H | Current rheumatology reports | 2017 | PMID: 28983775 |
Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. | Skrabl-Baumgartner A | Pediatric rheumatology online journal | 2017 | PMID: 28830446 |
ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. | Caorsi R | Annals of the rheumatic diseases | 2017 | PMID: 28522451 |
Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood. | Schepp J | Arthritis & rheumatology (Hoboken, N.J.) | 2017 | PMID: 28493328 |
Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases. | Nanthapisal S | Arthritis & rheumatology (Hoboken, N.J.) | 2016 | PMID: 27059682 |
Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. | Poswar Fde O | Journal of neurology | 2016 | PMID: 26914925 |
Mutations in CECR1 associated with a neutrophil signature in peripheral blood. | Belot A | Pediatric rheumatology online journal | 2014 | PMID: 25278816 |
Mutant ADA2 in vasculopathies. | Kastner DL | The New England journal of medicine | 2014 | PMID: 25075844 |
Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. | Navon Elkan P | The New England journal of medicine | 2014 | PMID: 24552285 |
Early-onset stroke and vasculopathy associated with mutations in ADA2. | Zhou Q | The New England journal of medicine | 2014 | PMID: 24552284 |
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Text-mined citations for rs202134424 ...
HelpRecord last updated Apr 15, 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.