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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000022.4(ADA):c.890C>T (p.Pro297Leu)

CA9871472

1505857 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7e93e86c-7843-4250-af1c-6654b389a610

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_000022.4:c.890C>T

NM_000022.4(ADA):c.890C>T (p.Pro297Leu)

NC_000020.11:g.44621103G>A

CM000682.2:g.44621103G>A

NC_000020.10:g.43249744G>A

CM000682.1:g.43249744G>A

NC_000020.9:g.42683158G>A

NG_007385.1:g.35633C>T

ENST00000372874.9:c.890C>T

ENST00000372874.8:c.890C>T

ENST00000372887.5:c.152-2830G>A

ENST00000464097.5:n.640C>T

ENST00000492931.5:n.1050C>T

ENST00000536532.5:c.*33C>T

ENST00000537820.1:c.818C>T

ENST00000539235.5:c.*274C>T

NM_000022.2:c.890C>T

NM_000022.3:c.890C>T

NM_001322050.1:c.485C>T

NM_001322051.1:c.818C>T

NR_136160.1:n.976C>T

NM_001322050.2:c.485C>T

NM_001322051.2:c.818C>T

NR_136160.2:n.917C>T

Likely Pathogenic

PM2_Supporting PS3_Supporting PM3 PP4_Moderate

PM5 BS3

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.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu). The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported. This variant was described in at least one patient in the literature, who presents *Reduced ADA enzyme activity in patient cells (1pt); *Reported also reported "a definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID: 34975878). The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence. In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported.

PS3_Supporting

The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence.

PM3

Proband 221 (see table 1) compound heterozygous for Leu304Arg (in trans - Likely Pathogenic according to SCID VCEP). 1 point, PM3_Moderate.

PP4_Moderate

PMID: 34975878: Reduced ADA enzyme activity in patient cells (1pt); Reported also "definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts) + SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate.

PM5

Another missense variant [c.890C>A (p.Pro297Gln] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not met).

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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