Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000022.4(ADA):c.872C>T (p.Ser291Leu)

CA252013

1971 (ClinVar)

Gene: ADA (HGNC:100)
Condition: adenosine deaminase deficiency (MONDO:0007064)
Inheritance Mode: Autosomal recessive inheritance
UUID: 9b0a8ddd-77c8-4aea-8b15-77dc875dcb7e
Approved on: 2026-05-12
Published on: 2026-05-20

HGVS expressions

NM_000022.4:c.872C>T
NM_000022.4(ADA):c.872C>T (p.Ser291Leu)
NC_000020.11:g.44621121G>A
CM000682.2:g.44621121G>A
NC_000020.10:g.43249762G>A
CM000682.1:g.43249762G>A
NC_000020.9:g.42683176G>A
NG_007385.1:g.35615C>T
ENST00000492931.6:n.1039C>T
ENST00000536076.2:c.719C>T
ENST00000536532.6:c.*15C>T
ENST00000537820.2:c.800C>T
ENST00000539235.6:c.*256C>T
ENST00000695889.1:c.347C>T
ENST00000695890.1:n.4367C>T
ENST00000695891.1:c.412C>T
ENST00000695927.1:c.950C>T
ENST00000695949.1:c.797C>T
ENST00000695956.1:c.27C>T
ENST00000695957.1:c.*363C>T
ENST00000695991.1:c.410C>T
ENST00000695992.1:c.*15C>T
ENST00000695993.1:c.872C>T
ENST00000695994.1:c.*15C>T
ENST00000695995.1:c.482C>T
ENST00000695996.1:n.954C>T
ENST00000696003.1:n.2656C>T
ENST00000696004.1:n.1040C>T
ENST00000696005.1:c.322C>T
ENST00000696006.1:c.*15C>T
ENST00000696007.1:c.799C>T
ENST00000696008.1:n.3226C>T
ENST00000696017.1:c.869C>T
ENST00000696034.1:c.*15C>T
ENST00000696035.1:n.1058C>T
ENST00000696036.1:n.1573C>T
ENST00000696037.1:n.2549C>T
ENST00000696038.1:c.*629C>T
ENST00000696039.1:n.1236C>T
ENST00000696058.1:c.869C>T
ENST00000696059.1:c.*817C>T
ENST00000696060.1:c.941C>T
ENST00000696061.1:c.869C>T
ENST00000696062.1:c.935C>T
ENST00000696063.1:c.947C>T
ENST00000696064.1:c.719C>T
ENST00000696065.1:c.194C>T
ENST00000696072.1:n.227C>T
ENST00000696073.1:n.1183C>T
ENST00000696074.1:n.423C>T
ENST00000696075.1:c.*842C>T
ENST00000696076.1:c.941C>T
ENST00000696077.1:c.866C>T
ENST00000696078.1:c.869C>T
ENST00000696079.1:c.869C>T
ENST00000696080.1:c.872C>T
ENST00000696081.1:n.991C>T
ENST00000696082.1:c.947C>T
ENST00000696083.1:n.1829C>T
ENST00000696084.1:n.1049C>T
ENST00000696104.1:c.556C>T
ENST00000372874.9:c.872C>T
ENST00000372874.8:c.872C>T
ENST00000372887.5:c.152-2812G>A
ENST00000464097.5:n.622C>T
ENST00000492931.5:n.1032C>T
ENST00000536532.5:c.*15C>T
ENST00000537820.1:c.800C>T
ENST00000539235.5:c.*256C>T
NM_000022.2:c.872C>T
NM_000022.3:c.872C>T
NM_001322050.1:c.467C>T
NM_001322051.1:c.800C>T
NR_136160.1:n.958C>T
NM_001322050.2:c.467C>T
NM_001322051.2:c.800C>T
NR_136160.2:n.899C>T
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PP4_Moderate PS3_Moderate PM3_Strong
Not Met criteria codes 21
PVS1 BS4 BS3 BS1 BS2 BP5 BP3 BP4 BP1 BP2 PS4 PS2 PS1 BA1 PP3 PP2 PP1 PM1 PM4 PM5 PM6

Evidence Links 0

Expert Panel

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
The c.872C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 291 (p.Ser291Leu). The groupmax filtering AF for genomes is 0.0000629 for this variant by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and there are no homozygous which meets PM2_Supporting. In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). One patient (P7, PMID: 19179314) who had this variant together with p.G216R met SCID diagnostic criteria = 0.5 pts + reduced ADA enzyme activity and increased dAdo nucleotides prior to treatment (Fig. 2E & 2F) = 5 pts + Use of enzyme replacement led to increased T cell numbers (Fig. 3B) = 4.5 pts. Total of 10 pts. But CNV information was not provided so the patient can only reach PP4 Moderate based on ADA specifications v2.1. This variant has been described in 4 compound heterozygous individuals: PMID: 26376800: Proband 6 compound heterozygous, in trans, for c.956_960del (p.Glu319fs) (At least Likely Pathogenic according to the SCID VCEP specifications [PM2_Supporting and PVS1]). 1 pt. PMID: 19179314: Patient compound heterozygous with variant G216R, phase unknown, Pathogenic according to SCID VCEP specifications 0.5 pts. PMID: 8227344: One patient heterozygous for Arg101Leu. Phase not confirmed. LP, according to SCID VCEP specifications, 0.25pts. AND PMID: 32307643: Patient is compound heterozygous with c.986C > T, p.A329V, Likely Pathogenic according to SCI VCEP specifications: Phase was not reported: 0.25pts. No homozygous has been described in the literature. The total is 2 pts, which is PM3_Strong. In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 2.1.0): PM2_Supporting, PS3_Moderate, PP4_Moderate, and PM3_Strong.
Met criteria codes
PM2_Supporting
The groupmax filtering AF for genomes is 0.0000629 for this variant by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and there are no homozygous which meets PM2_Supporting.
PP4_Moderate
"One patient (P7, PMID: 19179314) who had this variant together with p.G216R met SCID diagnostic criteria = 0.5 pts + reduced ADA enzyme activity and increased dAdo nucleotides prior to treatment (Fig. 2E & 2F) = 5 pts + Use of enzyme replacement led to increased T cell numbers (Fig. 3B) = 4.5 pts. Total of 10 pts. But CNV information was not provided so the patient can only reach PP4 Moderate based on ADA specifications v2.1.
PS3_Moderate
PMID: 9758612: activity of S291L 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.
PM3_Strong
PMID: 26376800: Proband 6 compound heterozygous, in trans, for c.956_960del (p.Glu319fs) (At least Likely Pathogenic according to the SCID VCEP specifications [PM2_Supporting and PVS1]). 1 pt. And PMID: 19179314: Patient compound heterozygous with variant G216R, phase unknown, Pathogenic According to SCID VCEP specifications 0.5 pts. PMID: 8227344: One patient heterozygous for Arg101Leu. Phase not confirmed. LP, according to SCID VCEP specifications, 0.25pts. PMID: 32307643: Patient is compound heterozygous with c.986C > T, p.A329V, Likely Pathogenic according to SCI VCEP specifications: Phase was not reported: 0.25pts. No homozygous was found in the literature. The total is 2 pts, which is PM3_Strong.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Another missense change at the same amino acid residue NM_000022.4(ADA):c.872C>G (p.Ser291Trp) VUS according to SCID VCEP specifications;
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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