Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000022.4(ADA):c.219-2A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA252010

1969 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 07d338de-c55f-43ab-bb35-f53075f9e0a3

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000022.4:c.219-2A>G

NM_000022.4(ADA):c.219-2A>G

NC_000020.11:g.44626601T>C

CM000682.2:g.44626601T>C

NC_000020.10:g.43255242T>C

CM000682.1:g.43255242T>C

NC_000020.9:g.42688656T>C

NG_007385.1:g.30135A>G

ENST00000372874.9:c.219-2A>G

ENST00000372874.8:c.219-2A>G

ENST00000492931.5:n.303-2A>G

ENST00000536076.1:n.399-2A>G

ENST00000536532.5:c.219-2A>G

ENST00000537820.1:c.219-2A>G

ENST00000539235.5:c.218+2446A>G

ENST00000545776.5:n.273-2A>G

NM_000022.2:c.219-2A>G

NM_000022.3:c.219-2A>G

NM_001322050.1:c.-71-2A>G

NM_001322051.1:c.219-2A>G

NR_136160.1:n.370-2A>G

NM_001322050.2:c.-71-2A>G

NM_001322051.2:c.219-2A>G

NR_136160.2:n.311-2A>G

Likely Pathogenic

PVS1_Strong PM3_Supporting PM2_Supporting

PS3 PP4

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000022.4:c.219-2A>G variant in ADA occurs within the canonical splice acceptor site (-2) of intron 3. It is predicted to cause skipping of biologically relevant exon 4, resulting in an in-frame deletion (removes amino acids 74-121), and the prediction is confirmed by RT-PCR (PMID 3182793). The variant removes >10% of the protein (48/363 amino acids) and the truncated region is critical to protein function (PMID 3182793) (PVS1_Strong). The variant has been detected in 1 individual with SCID who was homozygous for this variant (PMID 28266921) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Strong, PM3_Supporting, PM2_Supporting. (VCEP specifications version 1).

PVS1_Strong

PM3_Supporting

The variant has been detected in 1 individual with SCID. The individual was homozygous for this variant. (0.5pt, PM3_Supporting, PMID 28266921)

PM2_Supporting

This variant is absent from gnomAD v2.1.1. (PM2_Supporting)

PS3

The in vitro enzymatic activity assay shows that the truncation of exon 4 causes a decrease in ADA enzymatic activity (PMID 3182793). The level of activity reduction is not indicated in the report. And this result has been considered in the strength determination in PVS1 code. Therefore, PS3 is not met for this variant.

PP4

At least one patient with this variant displayed a T-B-NK- lymphocyte subset profile, which is highly specific for ADA SCID, however, counts only 0.5 points, not enough to reach PP4 at any strength of evidence. (PP4 is not met, PMID:28266921)

Curation History

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