ClinVar Miner

Submissions for variant NM_001282225.2(ADA2):c.562C>G (p.Leu188Val)

gnomAD frequency: 0.00006  dbSNP: rs765219776
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002264608 SCV002543394 uncertain significance Autoinflammatory syndrome 2016-12-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496197 SCV002803249 uncertain significance Sneddon syndrome; Vasculitis due to ADA2 deficiency 2021-11-02 criteria provided, single submitter clinical testing
Invitae RCV003746610 SCV004539153 likely pathogenic Vasculitis due to ADA2 deficiency 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the ADA2 protein (p.Leu188Val). This variant is present in population databases (rs765219776, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of polyarteritis nodosa (PMID: 30165497; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1694262). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 34004258). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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