VCV000120303.67 - ClinVar

NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)

Germline

Classification

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.

(23)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)

Variation ID: 120303 Accession: VCV000120303.67

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q11.1 22: 17207107 (GRCh38) [ NCBI UCSC ] 22: 17687997 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 10, 2018	Oct 20, 2024	Sep 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001282225.2:c.506G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001269154.1:p.Arg169Gln	missense
NM_001282226.2:c.506G>A	NP_001269155.1:p.Arg169Gln	missense
NM_001282227.2:c.380G>A	NP_001269156.1:p.Arg127Gln	missense
NM_001282228.2:c.380G>A	NP_001269157.1:p.Arg127Gln	missense
NM_001282229.2:c.146G>A	NP_001269158.1:p.Arg49Gln	missense
NC_000022.11:g.17207107C>T
NC_000022.10:g.17687997C>T
NG_033943.1:g.19748G>A
LRG_1217:g.19748G>A
LRG_1217t1:c.506G>A	LRG_1217p1:p.Arg169Gln

... more HGVS ... less HGVS

Protein change

R169Q, R127Q, R49Q

Other names

ADA2, ARG169GLN (rs77563738)

Canonical SPDI

NC_000022.11:17207106:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00031

The Genome Aggregation Database (gnomAD) 0.00041

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Links

ClinGen: CA150808 OMIM: 607575.0005 dbSNP: rs77563738 VarSome

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
Gene	OMIM	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.
ADA2		-	-	GRCh38 GRCh37	507	588

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.
Vasculitis due to ADA2 deficiency	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Sep 24, 2024	RCV000106384.25
Inherited Immunodeficiency Diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV001027542.3
Sneddon syndrome Vasculitis due to ADA2 deficiency	Likely pathogenic (1)	criteria provided, single submitter	Apr 29, 2022	RCV001536077.5
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Oct 1, 2022	RCV001091904.39
Sneddon syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jan 3, 2022	RCV001808328.3
Autoinflammatory syndrome	Likely pathogenic (1)	criteria provided, single submitter	Feb 17, 2017	RCV002262704.4
ADA2-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 6, 2024	RCV003945041.2

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.
Pathogenic (Nov 24, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Polyarteritis nodosa, childhoood-onset Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001448498.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Publications: PubMed (3) PubMed: 24552285‚ 26867732‚ 24552284 Comment: Variant summary: CECR1 c.506G>A (p.Arg169Gln) results in a conservative amino acid change in the encoded protein sequence. CECR1 is also known as ADA2 in the … (more) Variant summary: CECR1 c.506G>A (p.Arg169Gln) results in a conservative amino acid change in the encoded protein sequence. CECR1 is also known as ADA2 in the literature and databases. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251456 control chromosomes (gnomAD). c.506G>A has been reported (in both homozygous and compound heterozygous states) in the literature in individuals affected with Polyarteritis Nodosa, Childhoood-Onset (e.g. Elkan_2014, Zhou_2014) and ADA2-deficiency (e.g. VanMontfrans_2016). In many families, the variant was reported to segregate with disease. These data indicate that the variant is very likely to be associated with disease. In functional studies performed in both patient-derived cells and in cells transfected with the variant, c.506G>A resulted in reduced enzymatic activity as well as reduced protein secretion (e.g. VanMontfrans_2016, Elkan_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vasculitis due to ADA2 deficiency Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001469045.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021	Publications: PubMed (3) PubMed: 24552285‚ 25888558‚ 26867732 Comment: This ADA2 variant has been identified in numerous patients with ADA2-deficiency in both the compound heterozygous and homozygous state. ADA2 c.506G>A is located within the … (more) This ADA2 variant has been identified in numerous patients with ADA2-deficiency in both the compound heterozygous and homozygous state. ADA2 c.506G>A is located within the putative receptor-binding domain and functional studies have demonstrated that this variant causes severely decreased levels of secreted ADA2. This variant has been seen in trans with a second disease-causing ADA2 variant in affected individuals within a family. ADA2 c.506G>A (rs77563738) is present in a large population dataset (gnomAD: 134/282860 total alleles; 0.05%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be pathogenic. (less)
Pathogenic (Aug 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713079.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (12) PubMed: 24552285‚ 25083540‚ 25075845‚ 25075846‚ 24552284‚ 25457153‚ 25888558‚ 26922074‚ 26867732‚ 28993957‚ 28493328‚ 29391253 Comment: PS4, PS3_moderate, PM3, PP1_moderate, PP4 Number of individuals with the variant: 1
Likely pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sneddon syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002058153.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:24552285 PMID:24552285 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120303, PMID:24552285, PS1_S). In … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120303, PMID:24552285, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87, 3CNET: 0.971, PP3_P). A missense variant is a common mechanism associated with Sneddon syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Brisk reflexes (present) , Cerebral vasculitis (present) , Clonus (present) , Oculomotor apraxia (present) , Generalized hypotonia (present) , Stroke disorder (present)
Pathogenic (Jun 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vasculitis due to ADA2 deficiency Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059413.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Likely pathogenic (Feb 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002543392.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely pathogenic (Apr 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sneddon syndrome Vasculitis due to ADA2 deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752776.2 First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022
Pathogenic (Apr 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002499937.2 First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect; R169Q results in decreased ADA2 secretion and activity (Navon et al., 2014); In silico analysis supports that this … (more) Published functional studies demonstrate a damaging effect; R169Q results in decreased ADA2 secretion and activity (Navon et al., 2014); 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: 28830446, 27130863, 29271561, 25457153, 25075846, 25075845, 27663683, 25083540, 25888558, 24552285, 28993957, 24737293, 29736678, 25278816, 28974505, 29681619, 29391253, 29564582, 27059682, 28516235, 28493328, 28805790, 29273180, 29411230, 26867732, 26922074, 27514238, 28522451, 24552284, 30924144, 31393689, 33021335, 30386947, 31980526, 32353633, 33726816, 32499645, 32581362, 33757531, 33517505) (less)
Pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vasculitis due to ADA2 deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836134.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Vasculitis due to ADA2 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000773923.7 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 24552284‚ 24552285‚ 25888558‚ 26867732 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the ADA2 protein (p.Arg169Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the ADA2 protein (p.Arg169Gln). This variant is present in population databases (rs77563738, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ADA2-related conditions (PMID: 24552284, 24552285, 25888558, 26867732). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 120303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285, 26867732). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Inherited Immunodeficiency Diseases Affected status: yes Allele origin: germline	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001190112.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Clinical Features: Abnormality of B cell number (present) , Decreased number of CD4+ T cells (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency … (more) Abnormality of B cell number (present) , Decreased number of CD4+ T cells (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency (present) (less)
Pathogenic (Jun 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002067534.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the ADA2 gene demonstrated a sequence change, c.506G>A, in exon 3 that results in an amino acid change, p.Arg169Gln. This sequence … (more) DNA sequence analysis of the ADA2 gene demonstrated a sequence change, c.506G>A, in exon 3 that results in an amino acid change, p.Arg169Gln. This sequence change is a well-described pathogenic variant in both the homozygous and compound heterozygous state in individuals with ADA2-related disorders (PMID: 24552285, 28993957, 25457153, 29391253, 32499645, 26922074, 28493328, 30924144, 32353633). This sequence change has been described in the gnomAD database with frequency of 0.19% in the Finnish subpopulation (dbSNP rs77563738). The p.Arg169Gln change affects highly conserved amino acid residue located in a domain of the ADA2 protein that is known to be functional. Although, in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg169Gln substitution, experimental studies have demonstrated that this variant impacts ADA2 activity (PMID: 26867732, 24552285). (less)
Pathogenic (Sep 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vasculitis due to ADA2 deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005326547.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Clinical Features: Neutropenia (present)
Pathogenic (Oct 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248183.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: ADA2: PM1:Strong, PS1, PP1, PP2, PP4, PS3:Supporting Number of individuals with the variant: 5
Pathogenic (Mar 06, 2014)	no assertion criteria provided Method: literature only	VASCULITIS, AUTOINFLAMMATION, IMMUNODEFICIENCY, AND HEMATOLOGIC DEFECTS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000143888.4 First in ClinVar: Apr 01, 2014 Last updated: Nov 10, 2019	Publications: PubMed (3) PubMed: 24552284‚ 24552285‚ 26867732 Comment on evidence: In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified compound heterozygous mutations in the CECR1 gene: … (more) In a patient with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (VAIHS; 615688), Zhou et al. (2014) identified compound heterozygous mutations in the CECR1 gene: a c.506G-A transition in exon 3, resulting in an arg169-to-gln (R169Q) substitution in the PRB domain, and Y453C (607575.0001). Another patient with the disorder was compound heterozygous for R169Q and an intragenic 28-kb deletion. Both mutations occurred at highly conserved residues. Haplotype analysis indicated a founder effect for the R169Q mutation. The R169Q mutation was present in less than 1% of alleles in the 1000 Genomes Project and Exome Variant Server databases; it was not present in the ClinSeq 801 database. In 4 German sibs with polyarteritis nodosa, Navon Elkan et al. (2014) identified compound heterozygous mutations in the CECR1 gene: R169Q and a c.752C-T transition, resulting in a pro251-to-leu (P251L; 607575.0007) substitution at a highly conserved residue. Each unaffected parent was heterozygous for 1 of the mutations. Among 4,300 European controls, the R169Q variant was found in 7 (0.0008) and the P251L variant was found in 1 (0.0001). Serum ADA2 activity in patients was severely reduced compared to controls. The R169Q protein was barely detectable in transfected cells. Van Montfrans et al. (2016) identified a homozygous R169Q mutation in the ADA2 gene in 9 patients from 6 unrelated families from the Netherlands with highly variable presentations and manifestations. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. (less)
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Vasculitis due to ADA2 deficiency Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760481.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809536.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931243.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956731.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Sep 06, 2024)	no assertion criteria provided Method: clinical testing	ADA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004772741.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The ADA2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. This variant in the compound heterozygous or homozygous state has been … (more) The ADA2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. This variant in the compound heterozygous or homozygous state has been reported in patients with a complex immunologic and vascular phenotype, including polyarteritis nodosa (Navon Elkan et al. 2014. PubMed ID: 24552285; Van Eyck et al. 2015. PubMed ID: 25457153; Van Montfrans et al. 2016. PubMed ID: 26867732). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743921.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972920.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: literature only	Vasculitis due to ADA2 deficiency Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000994598.2 First in ClinVar: Oct 01, 2019 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 31393689‚ 26867732 BookShelf: NBK544951 BookShelf: NBK544951
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Comment:

Variant summary: CECR1 c.506G>A (p.Arg169Gln) results in a conservative amino acid change in the encoded protein sequence. CECR1 is also known as ADA2 in the literature and databases. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251456 control chromosomes (gnomAD). c.506G>A has been reported (in both homozygous and compound heterozygous states) in the literature in individuals affected with Polyarteritis Nodosa, Childhoood-Onset (e.g. Elkan_2014, Zhou_2014) and ADA2-deficiency (e.g. VanMontfrans_2016). In many families, the variant was reported to segregate with disease. These data indicate that the variant is very likely to be associated with disease. In functional studies performed in both patient-derived cells and in cells transfected with the variant, c.506G>A resulted in reduced enzymatic activity as well as reduced protein secretion (e.g. VanMontfrans_2016, Elkan_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This ADA2 variant has been identified in numerous patients with ADA2-deficiency in both the compound heterozygous and homozygous state. ADA2 c.506G>A is located within the putative receptor-binding domain and functional studies have demonstrated that this variant causes severely decreased levels of secreted ADA2. This variant has been seen in trans with a second disease-causing ADA2 variant in affected individuals within a family. ADA2 c.506G>A (rs77563738) is present in a large population dataset (gnomAD: 134/282860 total alleles; 0.05%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across most species assessed. We consider this variant to be pathogenic.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120303, PMID:24552285, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87, 3CNET: 0.971, PP3_P). A missense variant is a common mechanism associated with Sneddon syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate a damaging effect; R169Q results in decreased ADA2 secretion and activity (Navon et al., 2014); 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: 28830446, 27130863, 29271561, 25457153, 25075846, 25075845, 27663683, 25083540, 25888558, 24552285, 28993957, 24737293, 29736678, 25278816, 28974505, 29681619, 29391253, 29564582, 27059682, 28516235, 28493328, 28805790, 29273180, 29411230, 26867732, 26922074, 27514238, 28522451, 24552284, 30924144, 31393689, 33021335, 30386947, 31980526, 32353633, 33726816, 32499645, 32581362, 33757531, 33517505)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the ADA2 protein (p.Arg169Gln). This variant is present in population databases (rs77563738, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with ADA2-related conditions (PMID: 24552284, 24552285, 25888558, 26867732). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 120303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285, 26867732). For these reasons, this variant has been classified as Pathogenic.

Comment:

DNA sequence analysis of the ADA2 gene demonstrated a sequence change, c.506G>A, in exon 3 that results in an amino acid change, p.Arg169Gln. This sequence change is a well-described pathogenic variant in both the homozygous and compound heterozygous state in individuals with ADA2-related disorders (PMID: 24552285, 28993957, 25457153, 29391253, 32499645, 26922074, 28493328, 30924144, 32353633). This sequence change has been described in the gnomAD database with frequency of 0.19% in the Finnish subpopulation (dbSNP rs77563738). The p.Arg169Gln change affects highly conserved amino acid residue located in a domain of the ADA2 protein that is known to be functional. Although, in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg169Gln substitution, experimental studies have demonstrated that this variant impacts ADA2 activity (PMID: 26867732, 24552285).

Comment:

The ADA2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. This variant in the compound heterozygous or homozygous state has been reported in patients with a complex immunologic and vascular phenotype, including polyarteritis nodosa (Navon Elkan et al. 2014. PubMed ID: 24552285; Van Eyck et al. 2015. PubMed ID: 25457153; Van Montfrans et al. 2016. PubMed ID: 26867732). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
ADA2 deficiency: Clonal lymphoproliferation in a subset of patients.	Trotta L	The Journal of allergy and clinical immunology	2018	PMID: 29391253
Hematopoietic Stem Cell Transplantation in ADA2 Deficiency: Early Restoration of ADA2 Enzyme Activity and Disease Relapse upon Drop of Donor Chimerism.	Bucciol G	Journal of clinical immunology	2017	PMID: 28993957
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 2 Causes Antibody Deficiency.	Schepp J	Journal of clinical immunology	2016	PMID: 26922074
Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.	Van Montfrans JM	Rheumatology (Oxford, England)	2016	PMID: 26867732
Unexplained early-onset lacunar stroke and inflammatory skin lesions: Consider ADA2 deficiency.	Westendorp WF	Neurology	2015	PMID: 25888558
Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency.	Van Eyck L Jr	The Journal of allergy and clinical immunology	2015	PMID: 25457153
Mutant ADA2 in vasculopathies.	Segel R	The New England journal of medicine	2014	PMID: 25083540
Mutant ADA2 in vasculopathies.	Van Eyck L	The New England journal of medicine	2014	PMID: 25075846
Mutant ADA2 in vasculopathies.	van Montfrans J	The New England journal of medicine	2014	PMID: 25075845
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 rs77563738 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs77563738 ...