ClinVar Genomic variation as it relates to human health

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.

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.

ADA2: PM3:Strong, PS1, PM1, PM2, PM5

The observed missense variant c.139G>C(p.Gly47Arg) in ADA2 gene has been reported previously in homozygous state in multiple individuals with vasculitis (Clarke K, et al., 2019, Gibson KM, et al., 2019). The same amino acid change (c.139G>A, p.Gly47Arg) and other variant(s) that disrupt this residue have been determined to be pathogenic (Günthner R, et al., 2018). The c.139G>C(p.Gly47Arg) variant is reported with 0.002% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen-probably damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Gly at position 47 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Gly47Arg in ADA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.