Submissions for variant NM_001282225.2(ADA2):c.336C>G (p.His112Gln)

gnomAD frequency: 0.00002  dbSNP: rs587777241

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000106383	SCV000824039	pathogenic	Vasculitis due to ADA2 deficiency	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the ADA2 protein (p.His112Gln). This variant is present in population databases (rs587777241, gnomAD 0.004%). This missense change has been observed in individual(s) with ADA2-deficiency and early-onset stroke and polyarteritis nodosa (PMID: 24552284, 28493328). 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: 120302). 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%. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552284). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000722137	SCV000854421	pathogenic	not provided	2018-03-09	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262703	SCV002543385	likely pathogenic	Autoinflammatory syndrome	2022-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000722137	SCV003803199	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Published functional studies in zebrafish embryos demonstrate a damaging effect on protein function (Zhou et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28974505, 34324127, 34004258, 24552284, 30559313, 28493328, 27444081)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000106383	SCV003921893	pathogenic	Vasculitis due to ADA2 deficiency	2022-02-23	criteria provided, single submitter	clinical testing	0102 - Loss of function is a known mechanism of disease in this gene and is associated with vasculitis due to ADA2 deficiency (MONDO:0014306). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Significant phenotypic variability within families has been noted, with some asymptomatic individuals reported despite low enzyme levels (PMID: 27059682, 24552285). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in an annotated Zinc binding site (Pfam). (I) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(His112Tyr) variant was identified in an individual with ADA2 deficiency (PMID: 32892503). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with ADA2 deficiency in ClinVar and the literature (PMID: 30559313, 27444081, 28493328, 24552284). The phenotypes reported in these individuals were variable and included skin manifestations, immunodeficiency, neuropathy, anaemia, and stroke. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Affected individuals with this variant have low ADA2 enzyme activity, and this variant variant is unable to phenotypically rescue transgenic zebrafish (PMID: 24552284, 30559313, 27444081). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000106383	SCV000143887	pathogenic	Vasculitis due to ADA2 deficiency	2014-03-06	no assertion criteria provided	literature only