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

gnomAD frequency: 0.00041  dbSNP: rs77563738

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000106384	SCV000773923	pathogenic	Vasculitis due to ADA2 deficiency	2024-01-29	criteria provided, single submitter	clinical testing	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.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001027542	SCV001190112	likely pathogenic	Inherited Immunodeficiency Diseases	2019-01-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001091904	SCV001248183	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ADA2: PM1:Strong, PS1, PP1, PP2, PP4, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000106384	SCV001448498	pathogenic	Vasculitis due to ADA2 deficiency	2020-11-24	criteria provided, single submitter	clinical testing	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000106384	SCV001469045	pathogenic	Vasculitis due to ADA2 deficiency	2020-12-02	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001091904	SCV001713079	pathogenic	not provided	2019-08-19	criteria provided, single submitter	clinical testing	PS4, PS3_moderate, PM3, PP1_moderate, PP4
Fulgent Genetics, Fulgent Genetics	RCV001536077	SCV001752776	likely pathogenic	Sneddon syndrome; Vasculitis due to ADA2 deficiency	2022-04-29	criteria provided, single submitter	clinical testing
3billion	RCV001808328	SCV002058153	likely pathogenic	Sneddon syndrome	2022-01-03	criteria provided, single submitter	clinical testing	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.
Centogene AG - the Rare Disease Company	RCV000106384	SCV002059413	pathogenic	Vasculitis due to ADA2 deficiency	2017-06-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001091904	SCV002067534	pathogenic	not provided	2021-06-16	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV001091904	SCV002499937	pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	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)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262704	SCV002543392	likely pathogenic	Autoinflammatory syndrome	2017-02-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000106384	SCV003836134	pathogenic	Vasculitis due to ADA2 deficiency	2022-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945041	SCV004772741	pathogenic	ADA2-related condition	2024-02-27	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000106384	SCV000143888	pathogenic	Vasculitis due to ADA2 deficiency	2014-03-06	no assertion criteria provided	literature only
GeneReviews	RCV000106384	SCV000994598	not provided	Vasculitis due to ADA2 deficiency		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001091904	SCV001743921	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000106384	SCV001760481	likely pathogenic	Vasculitis due to ADA2 deficiency		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001091904	SCV001809536	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001091904	SCV001931243	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091904	SCV001956731	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091904	SCV001972920	pathogenic	not provided		no assertion criteria provided	clinical testing