Submissions for variant NM_001282225.2(ADA2):c.973-2A>G

gnomAD frequency: 0.00018  dbSNP: rs139750129

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652057	SCV000773925	pathogenic	Vasculitis due to ADA2 deficiency	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the ADA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). This variant is present in population databases (rs139750129, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with antibody deficiencies and vasculopathy (PMID: 28493328, 29963054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 541735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000652057	SCV001141327	pathogenic	Vasculitis due to ADA2 deficiency	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091903	SCV001248182	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001091903	SCV001713078	pathogenic	not provided	2020-03-17	criteria provided, single submitter	clinical testing	PVS1, PP1_strong, PS4_moderate, PP4
GeneDx	RCV001091903	SCV001790149	pathogenic	not provided	2024-06-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect. This splice site variant destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation (PMID: 29963054); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31393689, 31856934, 29391253, 28983775, 30386947, 29681619, 28493328, 31617030, 32535845, 34039731, 29963054)
Johns Hopkins Genomics, Johns Hopkins University	RCV000652057	SCV002570304	pathogenic	Vasculitis due to ADA2 deficiency	2022-04-29	criteria provided, single submitter	clinical testing	ADA2 c.973-2A>G has been identified in the homozygous and compound heterozygous state in multiple individuals with ADA2 deficiency and has been reported in ClinVar (Variation ID: 541735). This ADA2 variant (rs139750129) is rare (<0.1%) in a large population dataset (gnomAD: 37/282072 total alleles; 0.01312%; no homozygotes). Bioinformatic analysis predicts that this splice site variant will destroy the intron 5 canonical acceptor site and cause abnormal gene splicing. Two studies confirm that this variant is associated with ADA2 missplicing. We consider ADA2 c.973-2A>G to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499121	SCV002809725	pathogenic	Sneddon syndrome; Vasculitis due to ADA2 deficiency	2024-05-16	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225732	SCV003807803	pathogenic	Sneddon syndrome	2022-12-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 very strong, PP1 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000652057	SCV004122324	pathogenic	Vasculitis due to ADA2 deficiency	2023-10-23	criteria provided, single submitter	clinical testing	Variant summary: CECR1 c.973-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.00012 in 250678 control chromosomes (gnomAD). c.973-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Deficiency of adenosine deaminase-2 (example: Andriessen_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 37277582). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews	RCV000652057	SCV000994595	not provided	Vasculitis due to ADA2 deficiency		no assertion provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001091903	SCV001807159	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001091903	SCV001930101	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091903	SCV001952218	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411545	SCV004115426	pathogenic	ADA2-related disorder	2023-12-01	no assertion criteria provided	clinical testing	The ADA2 c.973-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the compound heterozygous or homozygous state in multiple individuals with antibody deficiency with vascular manifestations (Schepp et al. 2017. PubMed ID: 28493328; Trotta et al. 2018. PubMed ID: 29391253; Springer et al. 2018. PubMed ID: 29963054; Chong-Neto et al. 2019. PubMed ID: 31617030; van Well et al. 2019. PubMed ID: 31856934; Ganhão et al. 2020. PubMed ID: 32535845). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in ADA2 are expected to be pathogenic. This variant is interpreted as pathogenic.