ClinVar Genomic variation as it relates to human health

The heterozygous c.-47+2T>C variant in ADA2 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 640066, PMID: 35804211), in one individual with anemia. This individual also carried a pathogenic variant (ClinVar Variation ID: 640066, PMID: 35804211) variant, however the phase of these variants are unknown at this time. The c.-47+2T>C variant in ADA2 has been previously reported in three siblings with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome, and segregated with disease in these affected relatives from this one family reported (PMID: 32638197). These affected individuals who were previously reported were compound heterozygotes who carried a likely pathogenic variant in trans (PMID: 32638197), and the patient identified by our study was a presumed compound heterozygote who carried a likely pathogenic variant in unknown phase, which increases the likelihood that the c.-47+2T>C variant is pathogenic. This variant was absent from large population studies. RNAseq analysis performed on affected tissue showed evidence of substantially reduced levels of the mature ADA2 transcript and altered splicing in the residual pre-mRNAs, and RT-PCR analysis performed on affected tissue showed an approximately 50% decrease in ADA2 mRNA levels in individuals with the variant, as compared to unaffected controls (PMID: 32638197). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 75 bases from the intron-exon boundary, providing evidence that this variant may delete 25 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the ADA2 gene is an established disease mechanism in autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PS3_Moderate, PM2_Supporting, PM3, PP1 (Richards 2015).