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

dbSNP: rs202134424

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001390131	SCV001591764	pathogenic	Vasculitis due to ADA2 deficiency	2023-11-07	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 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 24552285, 24737293, 25075844, 27059682, 28522451, 28830446, 31008556, 31291964). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1076271). 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%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001535952	SCV001752613	pathogenic	Sneddon syndrome; Vasculitis due to ADA2 deficiency	2022-04-20	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001390131	SCV002540115	pathogenic	Vasculitis due to ADA2 deficiency		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264292	SCV002543371	pathogenic	Autoinflammatory syndrome	2021-10-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003334041	SCV004042140	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ADA2: PM3:Strong, PS1, PM1, PM2, PM5
PreventionGenetics, part of Exact Sciences	RCV003399212	SCV004105359	pathogenic	ADA2-related disorder	2023-04-17	criteria provided, single submitter	clinical testing	The ADA2 c.139G>C variant is predicted to result in the amino acid substitution p.Gly47Arg. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with ADA2-related disease (see for example - Nanthapisal et al. 2016. PubMed ID: 27059682; Skrabl-Baumgartner et al. 2017. PubMed ID: 28830446). Functional studies found this variant results in <20% of wild type activity (Jee et al. 2021. PubMed ID: 34004258). Additionally, an alternate nucleotide substitution (c.139G>A) resulting in the same missense variant and alternate missense variants affecting this residue (p.Gly47Trp, p.Gly47Ala, p.Gly47Val) have been reported as pathogenic (Karacan et al. 2019. PubMed ID: 30783801; Jee et al. 2021. PubMed ID: 34004258). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-17690429-C-G). This variant is interpreted as pathogenic.
Revvity Omics, Revvity	RCV003334041	SCV004234709	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing