ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.975+1G>A

dbSNP: rs2065325898
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV001729828 SCV004809082 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2024-02-21 reviewed by expert panel curation The c.975+1G>A (NM_000022.4) variant in ADA occurs within the canonical splice site donor of intron 10. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 2/1111992 alleles) of the c.975+1G>A variant in ADA is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. At least one patient with this variant displayed * Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), which is highly specific for ADA SCID (PP4_Moderate, PMID: 8227344). In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1, PM2_Supporting, and PP4_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001732098 SCV001442585 pathogenic Severe combined immunodeficiency disease 2020-10-01 criteria provided, single submitter clinical testing Variant summary: ADA c.975+1G>A 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 that the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Santisteban_1993). The variant was absent in 251494 control chromosomes. c.975+1G>A has been reported in the literature in at least one individual affected with immunodeficiency (Santisteban_1993, subsequently cited by others including Arredondo-Vega_1998, Felgentreff_2011). Santisteban et al, 1993 also report that the variant was inactive in functional studies, however this data was not shown, and thus was not used for evidence in the context of this classification. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV001729828 SCV001977448 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2021-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001729828 SCV002783911 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2021-07-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001729828 SCV004298085 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2023-06-03 criteria provided, single submitter clinical testing Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 8227344). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 984454). This variant is also known as IVS 10+1G>A. Disruption of this splice site has been observed in individual(s) with severe combined immunodeficiency (PMID: 8227344). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the ADA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

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