Submissions for variant NM_001282225.2(ADA2):c.139G>A (p.Gly47Arg)

gnomAD frequency: 0.00010  dbSNP: rs202134424

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000106385	SCV000784564	likely pathogenic	Vasculitis due to ADA2 deficiency	2018-03-05	criteria provided, single submitter	clinical testing
Invitae	RCV000106385	SCV000941825	pathogenic	Vasculitis due to ADA2 deficiency	2023-12-26	criteria provided, single submitter	clinical testing	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000106385	SCV000992340	pathogenic	Vasculitis due to ADA2 deficiency	2019-03-27	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000106385	SCV001141328	pathogenic	Vasculitis due to ADA2 deficiency	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091906	SCV001248185	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ADA2: PS1, PM1, PM2, PM3, PM5, PS3:Supporting
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000106385	SCV001547502	pathogenic	Vasculitis due to ADA2 deficiency	2021-03-19	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000106385	SCV002073342	pathogenic	Vasculitis due to ADA2 deficiency		criteria provided, single submitter	clinical testing	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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000106385	SCV002099533	pathogenic	Vasculitis due to ADA2 deficiency	2022-02-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262705	SCV002543370	pathogenic	Autoinflammatory syndrome	2021-11-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498474	SCV002811609	pathogenic	Sneddon syndrome; Vasculitis due to ADA2 deficiency	2021-12-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003445509	SCV004171922	pathogenic	Sneddon syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000106385	SCV004803992	pathogenic	Vasculitis due to ADA2 deficiency	2024-01-30	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000106385	SCV004807021	pathogenic	Vasculitis due to ADA2 deficiency	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000106385	SCV000143889	pathogenic	Vasculitis due to ADA2 deficiency	2014-03-06	no assertion criteria provided	literature only
GeneReviews	RCV000106385	SCV000994596	not provided	Vasculitis due to ADA2 deficiency		no assertion provided	literature only