Submissions for variant NM_001282225.2(ADA2):c.1397_1403del (p.Lys466fs)

dbSNP: rs754904956

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001066294	SCV001231301	pathogenic	Vasculitis due to ADA2 deficiency	2022-07-05	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs754904956, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ADA2 protein in which other variant(s) (p.Asn491Lysfs*16) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 860051). This variant is also known as 17662748:GTCAGCCT>G. This premature translational stop signal has been observed in individual(s) with bone marrow failure, Diamond-Blackfan anemia, and/or primary immunodeficiency (PMID: 30503522, 31945408, 32888943). This sequence change creates a premature translational stop signal (p.Lys466Thrfs*2) in the ADA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the ADA2 protein.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264175	SCV002543369	likely pathogenic	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151275	SCV003839315	likely pathogenic	not provided	2022-07-21	no assertion criteria provided	clinical testing	DNA sequence analysis of the ADA2 gene demonstrated a 7 base pair deletion in exon 9, c.1397_1403del. This sequence change results in an amino acid frameshift and creates a premature stop codon one amino acid downstream of the change, p.Lys466Thrfs*2. While this sequence change is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last few amino acid(s) of the ADA2 protein. This sequence change has been described in the homozygous state in one individual with pure red cell aplasia and bone marrow failure and shown to have no ADA2 enzyme activity in vitro (PMID 31945408) and has also been described in three individuals in the homozygous state with Diamond Blackfan Anemia (PMID 30503522) and in one individual with primary immunodeficiency (PMID: 32888943). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004% (dbSNP rs754904956). These collective evidences indicate that this sequence change is likely pathogenic.