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.445C>T (p.Arg149Trp)

CA266014

68264 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 66e50984-088e-48e7-b034-9faab22a49dc

HGVS expressions

NM_000022.4:c.445C>T

NM_000022.4(ADA):c.445C>T (p.Arg149Trp)

NC_000020.11:g.44625602G>A

CM000682.2:g.44625602G>A

NC_000020.10:g.43254243G>A

CM000682.1:g.43254243G>A

NC_000020.9:g.42687657G>A

NG_007385.1:g.31134C>T

ENST00000372874.9:c.445C>T

ENST00000372874.8:c.445C>T

ENST00000464097.5:n.119C>T

ENST00000492931.5:n.529C>T

ENST00000536532.5:c.445C>T

ENST00000537820.1:c.445C>T

ENST00000539235.5:c.219-2524C>T

NM_000022.2:c.445C>T

NM_000022.3:c.445C>T

NM_001322050.1:c.73+854C>T

NM_001322051.1:c.445C>T

NR_136160.1:n.596C>T

NM_001322050.2:c.73+854C>T

NM_001322051.2:c.445C>T

NR_136160.2:n.537C>T

Likely Pathogenic

PM2 PP4_Moderate PS3_Moderate

PM5 BS1

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.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID: 10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. 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: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0).

PM2

Overall allele frequency on gnomAD is 0.00001648 (4/242700 alleles) the highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population (https://gnomad.broadinstitute.org/variant/20-43254243-G-A - No homozygous), which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met.

PP4_Moderate

PMID: 10200056: Patient CS with diagnosis of SCID and pretreatment RBC dAXP of 41.5% (normal is <0.2% as per PMID). Under ClinGen SCID VCEP ADA PP4 specifications, this is worth 2 points. 2 or more points is sufficient to meet PP4_Moderate criteria, therefore PP4 is applied at moderate strength.

PS3_Moderate

PMID: 9758612: activity of Arg149Trp is in group 1 which has 0.012% activity vs WT. This is below the threshold set for ADA PS3_Moderate by the ClinGen SCID VCEP (PS3_Moderate < 0.05% of wild type activity (group I)). Therefore PS3 is met at moderate strength.

PM5

Two additional missense variants in the same codon: * NM_000022.4(ADA):c.446G>A (p.Arg149Gln): VUS according SCID VCEP * NM_000022.4(ADA):c.446G>T (p.Arg149Leu), VUS according SCID VCEP PM5 is not met.

BS1

Allele frequency in gnomAD does not exceed threshold set by SCID VCEP ADA specifications (gnomAD popmax filtering allele frequency >0.00161), therefore BS1 is not met

Approved on: 2024-01-16

Published on: 2024-01-16

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