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.935A>G (p.Lys312Arg)

CA9871464

1507601 (ClinVar)

Gene: ADA (HGNC:100)

Condition: adenosine deaminase deficiency (MONDO:0007064)

Inheritance Mode: Autosomal recessive inheritance

UUID: ec440f51-ed74-4a57-9e84-f4c2fb2dce19

Approved on: 2024-04-23

Published on: 2024-04-23

HGVS expressions

NM_000022.4:c.935A>G

NM_000022.4(ADA):c.935A>G (p.Lys312Arg)

NC_000020.11:g.44621058T>C

CM000682.2:g.44621058T>C

NC_000020.10:g.43249699T>C

CM000682.1:g.43249699T>C

NC_000020.9:g.42683113T>C

NG_007385.1:g.35678A>G

ENST00000492931.6:n.1102A>G

ENST00000536076.2:c.782A>G

ENST00000536532.6:c.*78A>G

ENST00000537820.2:c.863A>G

ENST00000539235.6:c.*319A>G

ENST00000695889.1:c.410A>G

ENST00000695890.1:n.4430A>G

ENST00000695891.1:c.475A>G

ENST00000695927.1:c.1013A>G

ENST00000695949.1:c.860A>G

ENST00000695956.1:c.90A>G

ENST00000695957.1:c.*426A>G

ENST00000695991.1:c.473A>G

ENST00000695992.1:c.*78A>G

ENST00000695993.1:c.935A>G

ENST00000695994.1:c.*78A>G

ENST00000695995.1:c.545A>G

ENST00000695996.1:n.1017A>G

ENST00000696003.1:n.2719A>G

ENST00000696004.1:n.1103A>G

ENST00000696005.1:c.385A>G

ENST00000696006.1:c.*78A>G

ENST00000696007.1:c.862A>G

ENST00000696008.1:n.3289A>G

ENST00000696017.1:c.932A>G

ENST00000696034.1:c.*78A>G

ENST00000696035.1:n.1121A>G

ENST00000696036.1:n.1636A>G

ENST00000696037.1:n.2612A>G

ENST00000696038.1:c.*692A>G

ENST00000696039.1:n.1299A>G

ENST00000696058.1:c.932A>G

ENST00000696059.1:c.*880A>G

ENST00000696060.1:c.1004A>G

ENST00000696061.1:c.932A>G

ENST00000696062.1:c.998A>G

ENST00000696063.1:c.1010A>G

ENST00000696064.1:c.782A>G

ENST00000696065.1:c.257A>G

ENST00000696072.1:n.290A>G

ENST00000696073.1:n.1246A>G

ENST00000696074.1:n.486A>G

ENST00000696075.1:c.*905A>G

ENST00000696076.1:c.1004A>G

ENST00000696077.1:c.929A>G

ENST00000696078.1:c.932A>G

ENST00000696079.1:c.932A>G

ENST00000696080.1:c.935A>G

ENST00000696081.1:n.1054A>G

ENST00000696082.1:c.1010A>G

ENST00000696083.1:n.1892A>G

ENST00000696084.1:n.1112A>G

ENST00000696104.1:c.*4A>G

ENST00000372874.9:c.935A>G

ENST00000372874.8:c.935A>G

ENST00000372887.5:c.152-2875T>C

ENST00000464097.5:n.685A>G

ENST00000492931.5:n.1095A>G

ENST00000536532.5:c.*78A>G

ENST00000537820.1:c.863A>G

ENST00000539235.5:c.*319A>G

NM_000022.2:c.935A>G

NM_000022.3:c.935A>G

NM_001322050.1:c.530A>G

NM_001322051.1:c.863A>G

NR_136160.1:n.1021A>G

NM_001322050.2:c.530A>G

NM_001322051.2:c.863A>G

NR_136160.2:n.962A>G

Uncertain Significance

PM2_Supporting

PM5

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 c.935A>G (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 312 (p.Lys312Arg). The filtering allele frequency (the upper threshold of the 95% CI of (4/418132 alleles) of the c.935A>G variant in ADA is 0.000003240 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. Another missense variant [c.934A>C, p.Lys312Gln] in the same codon has been reported; however, the ClinGen SCID VCEP classified this variant as VUS (PM5 not met). To our knowledge, this variant has not been reported in the literature in individuals affected with ADA-related conditions or in functional studies. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting.

PM2_Supporting

The filtering allele frequency (the upper threshold of the 95% CI of (4/418132 alleles) of the c.935A>G variant in ADA is 0.000003240 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.

PM5

Another missense variant [c.934A>C, p.Lys312Gln] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met).

Curation History

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