Submissions for variant NM_001282225.2(ADA2):c.144del (p.Arg49fs)

dbSNP: rs756881285

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793011	SCV000932344	pathogenic	Vasculitis due to ADA2 deficiency	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg49Glyfs*4) in the ADA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). This variant is present in population databases (rs780731346, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with polyarteritis nodosa or symptoms consistent with polyarteritis nodosa (PMID: 27059682, 28522451). This variant is also known as c.138/144delG. ClinVar contains an entry for this variant (Variation ID: 640066). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002487649	SCV002776723	pathogenic	Sneddon syndrome; Vasculitis due to ADA2 deficiency	2021-11-19	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000793011	SCV003922186	pathogenic	Vasculitis due to ADA2 deficiency	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Arg49GlyfsTer4 variant in ADA2 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 624611), in one individual with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 624611). The p.Arg49GlyfsTer4 variant in ADA2 has been previously reported in 4 unrelated individuals with vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (PMID: 32909274, PMID: 35804211, PMID: 28522451, PMID: 27059682) and segregated with disease in 2 affected relatives from one family (PMID: 35804211), but has been identified in 0.007% (3/41374) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756881285). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 previously reported unrelated individuals (PMID: 32909274, PMID: 35804211, PMID: 28522451, PMID: 27059682), one was a homozygote (PMID: 35804211) and two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 27059682, ClinVar Variation ID: 1407177; PMID: 28522451, ClinVar Variation ID 189342), which increases the likelihood that the p.Arg49GlyfsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 640066) and has been interpreted as pathogenic by Invitae and Fulgent Genetics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 49 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADA2 gene is strongly associated to autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_Strong (Richards 2015).