ClinVar Genomic variation as it relates to human health

Observed with a pathogenic variant on the opposite allele (in trans) in a patient with features consistent with ADA2 deficiency referred for genetic testing at GeneDx and observed with a second variant in individuals from published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 28974505, 33757531, 33529688); Published functional studies demonstrate a damaging effect: reduced ADA2 enzymatic activity (PMID: 33529688, 34004258); 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: 36807221, 34324127, 34426522, 30503522, 31043544, 28974505, 32892503, 33529688, 33757531, 34004258, 28805790, 31015188, 31945408)

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 358 of the ADA2 protein (p.Gly358Arg). This variant is present in population databases (rs45511697, gnomAD 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 28805790, 28974505, 30503522, 31015188, 31043544). 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: 420337). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

The ADA2 c.1072G>A variant is predicted to result in the amino acid substitution p.Gly358Arg. This variant in the homozygous condition or along with a second variant in this gene was reported in multiple individuals with ADA2-deficiency/Diamond-Blackfan anemia (see examples: Table 2, Hashem et al. 2017. PubMed ID: 28974505; Reported as CECR1 chr22:17669238:C>T in Table 3, Ulirsch et al. 2018. PubMed ID: 30503522; Table 3 and 4, Özen et al. 2020. PubMed ID: 31043544; Table S5, Sharma et al. 2020. PubMed ID: 32892503; Table 1, Nihira et al. 2021. PubMed ID: 33529688; Table 2, Wang et al. 2021. PubMed ID: 33757531). Functional studies suggest that this variant led to low level of ADA2 plasma activity (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/22-17669238-C-T). This variant is interpreted as pathogenic.

Variant summary: ADA2 c.1072G>A (p.Gly358Arg), also reported as G316R, results in a non-conservative amino acid change located in the Adenosine deaminase domain (IPR001365) 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 2e-05 in 1613038 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADA2 causing Vasculitis due to ADA2 deficiency (2e-05 vs 0.0011). c.1072G>A has been reported in the literature in the presumed compound heterozygous or homozygous state in multiple individuals affected with ADA2 deficiency (example, Kaljas_2017, Simon_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in vitro (example, Jee_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34004258, 27663683, 32135276). ClinVar contains an entry for this variant (Variation ID: 420337). Based on the evidence outlined above, the variant was classified as pathogenic.