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]

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Variant: NM_000022.4(ADA):c.446G>A (p.Arg149Gln)

CA115281

1963 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ceb546d2-46b3-473c-a5e0-c41a6688ecf0

HGVS expressions

NM_000022.4:c.446G>A

NM_000022.4(ADA):c.446G>A (p.Arg149Gln)

NC_000020.11:g.44625601C>T

CM000682.2:g.44625601C>T

NC_000020.10:g.43254242C>T

CM000682.1:g.43254242C>T

NC_000020.9:g.42687656C>T

NG_007385.1:g.31135G>A

ENST00000372874.9:c.446G>A

ENST00000372874.8:c.446G>A

ENST00000464097.5:n.120G>A

ENST00000492931.5:n.530G>A

ENST00000536532.5:c.446G>A

ENST00000537820.1:c.446G>A

ENST00000539235.5:c.219-2523G>A

NM_000022.2:c.446G>A

NM_000022.3:c.446G>A

NM_001322050.1:c.73+855G>A

NM_001322051.1:c.446G>A

NR_136160.1:n.597G>A

NM_001322050.2:c.73+855G>A

NM_001322051.2:c.446G>A

NR_136160.2:n.538G>A

Uncertain Significance

BS3_Supporting PM5_Supporting

PM6 PM2 PM3 PS2 PS3 PS1 PP4 PP1

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(ADA):c.446G>A (p.Arg149Gln) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 149 (p.Arg149Gln). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/107374 observed alleles) is 0.000003610 on gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742). However, we can not use this evidence because it has a filter warning (RF). Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612, BS3_moderate). At least one additional missense variant was observed as LP according to SCID VCEP specifications version (PM5_supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS3_Supporting, and PM5_Suppoting. (VCEP specifications version 1).

BS3_Supporting

Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612)(BS3_Supporting).

PM5_Supporting

Was find two additional missense variants in the same codon: * NM_000022.4(ADA):c.445C>T (p.Arg149Trp): LP according to the SCID VCEP specifications version PILOT, PM5_Supporting * NM_000022.4(ADA):c.446G>T (p.Arg149Leu): VUS according to the SCID VCEP specifications version PILOT. Does not count for PM5.

PM6