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.716G>A (p.Gly239Asp)

CA409120283

555264 (ClinVar)

Gene: ADA (HGNC:100)

Condition: adenosine deaminase deficiency (MONDO:0007064)

Inheritance Mode: Autosomal recessive inheritance

UUID: 0289f8a6-401a-4de5-b9c9-811f04dbbdc7

Approved on: 2025-11-04

Published on: 2025-11-21

HGVS expressions

NM_000022.4:c.716G>A

NM_000022.4(ADA):c.716G>A (p.Gly239Asp)

NC_000020.11:g.44622893C>T

CM000682.2:g.44622893C>T

NC_000020.10:g.43251534C>T

CM000682.1:g.43251534C>T

NC_000020.9:g.42684948C>T

NG_007385.1:g.33843G>A

ENST00000492931.6:n.883G>A

ENST00000536076.2:c.563G>A

ENST00000536532.6:c.716G>A

ENST00000537820.2:c.644G>A

ENST00000539235.6:c.*100G>A

ENST00000695889.1:c.256G>A

ENST00000695890.1:n.2595G>A

ENST00000695891.1:c.256G>A

ENST00000695927.1:c.794G>A

ENST00000695949.1:c.641G>A

ENST00000695957.1:c.*207G>A

ENST00000695991.1:c.254G>A

ENST00000695992.1:c.716G>A

ENST00000695993.1:c.716G>A

ENST00000695994.1:c.689G>A

ENST00000695995.1:c.326G>A

ENST00000695996.1:n.863G>A

ENST00000696003.1:n.884G>A

ENST00000696004.1:n.884G>A

ENST00000696005.1:c.166G>A

ENST00000696006.1:c.644G>A

ENST00000696007.1:c.643G>A

ENST00000696008.1:n.3070G>A

ENST00000696017.1:c.713G>A

ENST00000696034.1:c.716G>A

ENST00000696035.1:n.902G>A

ENST00000696036.1:n.1482G>A

ENST00000696037.1:n.2393G>A

ENST00000696038.1:c.*538G>A

ENST00000696039.1:n.1080G>A

ENST00000696058.1:c.713G>A

ENST00000696059.1:c.*661G>A

ENST00000696060.1:c.785G>A

ENST00000696061.1:c.713G>A

ENST00000696062.1:c.779G>A

ENST00000696063.1:c.791G>A

ENST00000696064.1:c.563G>A

ENST00000696065.1:c.103G>A

ENST00000696073.1:n.1027G>A

ENST00000696074.1:n.332G>A

ENST00000696075.1:c.*686G>A

ENST00000696076.1:c.785G>A

ENST00000696077.1:c.710G>A

ENST00000696078.1:c.713G>A

ENST00000696079.1:c.713G>A

ENST00000696080.1:c.716G>A

ENST00000696081.1:n.835G>A

ENST00000696082.1:c.791G>A

ENST00000696083.1:n.1673G>A

ENST00000696084.1:n.893G>A

ENST00000696104.1:c.400G>A

ENST00000372874.9:c.716G>A

ENST00000372874.8:c.716G>A

ENST00000372887.5:c.152-1040C>T

ENST00000464097.5:n.466G>A

ENST00000492931.5:n.876G>A

ENST00000536532.5:c.716G>A

ENST00000537820.1:c.644G>A

ENST00000539235.5:c.*100G>A

NM_000022.2:c.716G>A

NM_000022.3:c.716G>A

NM_001322050.1:c.311G>A

NM_001322051.1:c.644G>A

NR_136160.1:n.867G>A

NM_001322050.2:c.311G>A

NM_001322051.2:c.644G>A

NR_136160.2:n.808G>A

Pathogenic

PM2_Supporting PP4_Moderate PM3_Very Strong

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 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

NM_000022.4:c.716G>A is a missense variant predicted to cause the substitution of Glycine by Aspartic acid at amino acid 239 (p.Gly239Asp). The highest population minor allele frequency in gnomAD v4 is 0.00001098 (1/91084 alleles) in the South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.1.0. Patient #12, 13 and 26 (PMID: 26255240) presented with: Reduced ADA enzyme activity in patient cells and increased dAdo nucleotides (dATP) in pretreatment erythrocytes (5 pts.) (PP4_Moderate; total: 5 pts). This variant has been observed to be homozygous in many individuals affected with ADA-deficient severe combined immunodeficiency (PMIDs: 31858364, 32307643, 26255240, and 30858051). Four of them are from consanguineous families: 0.5 pts each, 2 pts. Five of them are from non-consanguineous families. However, the five individuals are reported by two teams from the same hospital (PMIDs: 26255240, 31858364). To avoid potential unreported overlap of probands, only one report is counted (PMID: 26255240). 1 pt each, 3 pts. 5 points in total, PM3_Very_Strong. In summary, this variant meets the criteria to be classified as Pathogenic variant for autosomal recessive adenosine deaminase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4_Moderate, and PM3_Very_Strong (VCEP specifications version 2.1).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001098 (1/91084 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD v4.1.0.

PP4_Moderate

Patient #12, 13 and 26 (PMID: 26255240) presented with: Reduced ADA enzyme activity in patient cells and increased dAdo nucleotides (dATP) in pretreatment erythrocytes (5 pts.) (PP4_moderate; total: 5 pts).

PM3_Very Strong

This variant has been observed to be homozygous in many individuals affected with ADA-deficient severe combined immunodeficiency (PMIDs: 31858364, 32307643, 26255240, and 30858051). Four of them are from consanguineous families: 0.5 pts each, 2 pts. Five of them are from non-consanguineous families. However, the five individuals are reported by two teams from the same hospital (PMIDs 26255240, 31858364). To avoid potential unreported overlap of probands, only one report is counted (PMID 26255240). 1 pt each, 3 pts. 5 points in total, PM3_Very_Strong.

Curation History

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