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_000022.2(ADA):c.986C>T

CA252004

1959 (ClinVar)

Gene: ADA
Condition: adenosine deaminase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 53a1d4d0-400f-4dd7-b6be-64e58c217a17
Approved on: 2024-02-21
Published on: 2024-10-30

HGVS expressions

NM_000022.2:c.986C>T
NM_000022.2(ADA):c.986C>T
NC_000020.11:g.44620391G>A
CM000682.2:g.44620391G>A
NC_000020.10:g.43249032G>A
CM000682.1:g.43249032G>A
NC_000020.9:g.42682446G>A
NG_007385.1:g.36345C>T
ENST00000492931.6:n.1153C>T
ENST00000536076.2:c.833C>T
ENST00000536532.6:c.*129C>T
ENST00000537820.2:c.914C>T
ENST00000539235.6:c.*370C>T
ENST00000695889.1:c.461C>T
ENST00000695890.1:n.5097C>T
ENST00000695891.1:c.526C>T
ENST00000695927.1:c.1064C>T
ENST00000695949.1:c.911C>T
ENST00000695956.1:c.141C>T
ENST00000695957.1:c.*477C>T
ENST00000695991.1:c.524C>T
ENST00000695992.1:c.*129C>T
ENST00000695993.1:c.986C>T
ENST00000695994.1:c.*129C>T
ENST00000695995.1:c.596C>T
ENST00000695996.1:n.1068C>T
ENST00000696003.1:n.2770C>T
ENST00000696004.1:n.1770C>T
ENST00000696005.1:c.436C>T
ENST00000696006.1:c.*129C>T
ENST00000696007.1:c.913C>T
ENST00000696008.1:n.3340C>T
ENST00000696017.1:c.983C>T
ENST00000696034.1:c.*129C>T
ENST00000696035.1:n.1172C>T
ENST00000696036.1:n.1687C>T
ENST00000696037.1:n.2663C>T
ENST00000696038.1:c.*743C>T
ENST00000696039.1:n.1350C>T
ENST00000696058.1:c.983C>T
ENST00000696059.1:c.*931C>T
ENST00000696060.1:c.1055C>T
ENST00000696061.1:c.983C>T
ENST00000696062.1:c.1049C>T
ENST00000696063.1:c.1061C>T
ENST00000696064.1:c.833C>T
ENST00000696065.1:c.308C>T
ENST00000696072.1:n.341C>T
ENST00000696073.1:n.1297C>T
ENST00000696074.1:n.537C>T
ENST00000696075.1:c.*956C>T
ENST00000696076.1:c.1055C>T
ENST00000696077.1:c.980C>T
ENST00000696078.1:c.983C>T
ENST00000696079.1:c.983C>T
ENST00000696080.1:c.986C>T
ENST00000696081.1:n.1105C>T
ENST00000696082.1:c.1061C>T
ENST00000696083.1:n.1943C>T
ENST00000696084.1:n.1163C>T
ENST00000696104.1:c.*55C>T
ENST00000372874.9:c.986C>T
ENST00000372874.8:c.986C>T
ENST00000372887.5:c.152-3542G>A
ENST00000464097.5:n.1352C>T
ENST00000492931.5:n.1146C>T
ENST00000536532.5:c.*129C>T
ENST00000537820.1:c.914C>T
ENST00000539235.5:c.*370C>T
NM_000022.3:c.986C>T
NM_001322050.1:c.581C>T
NM_001322051.1:c.914C>T
NR_136160.1:n.1072C>T
NM_000022.4:c.986C>T
NM_001322050.2:c.581C>T
NM_001322051.2:c.914C>T
NR_136160.2:n.1013C>T
More

Pathogenic

Met criteria codes 5
PP4_Moderate PM6 PS3_Moderate PM2_Supporting PM3_Strong
Not Met criteria codes 4
PS1 PM5 BA1 BS1

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 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Severe Combined Immunodeficiency Disease VCEP
The c.986C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 329 (p.Ala329Val). The filtering allele frequency (the upper threshold of the 95% CI of 37/74910) of the c.986C>T variant in ADA is 0.0003683 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore do not meet this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. In vitro experiments of ADA activity in E. coli demonstrated a percentage of wild-type (wt) activity ranging from 0.1% to 5.1%, with an average ± standard deviation of 1.2% ± 1.4%. This finding classifies the variant into Group I, suggesting a significant impact on protein function. (PS3_Moderate; PMID 9758612). This variant has been detected in many individuals in the literature. Evaluated here four patients with ADA-SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant: * PMID 8614422, compound heterozygous with p.Gly74Val (at least likely pathogenic according to SCID VCEP specifications, Phase is not confirmed = 0.25pt; * PMID 32307643, compound heterozygous with p.Ser291Leu (at least likely pathogenic according to SCID VCEP specifications. Phase is not confirmed = 0.25pt; * PMID: 8401541, Proband 1 is comp. het. A329V and Q254X (at least likely pathogenic according to SCID VCEP specifications - PM2_Supporting and PVS1) - phase (in trans) confirmed = 1pt; Additionally, 01 individual was homozygous for the variant = 0.5 pts (PMID: 1346349). The total is 2 points, PM3_Strong. Patient from PMID 8614422 presented: * ADA activity in patient RBCs was undetectable (1pt), * Concentration of total deoxyadenosine nucleotides was elevated (2pt). * ADA-SCID phenotypes of the patient were corrected by PEG-ADA supplement (1pt). Total = 4 points, PP4_Moderate. PMID: 8614422. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 01 individual with ADA-SCID, with phenotype highly specific for the gene (PM6_Moderate, PMID: 1346349). In summary, this variant is classified as Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PS3_Moderate, PM3_Strong, PP4_Moderate, and PM6_Moderate.
Met criteria codes
PP4_Moderate
Patient from PMID 8614422 presented: The ADA activity in patient RBCs was undetectable (1pt), and the concentration of total deoxyadenosine nucleotides was elevated (2pt). The ADA-SCID phenotypes of the patient were corrected by PEG-ADA supplement (1pt). Total = 4 points, PP4_Moderate. PMID: 8614422.
PM6
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 01 individual with ADA-SCID, with phenotype highly specific for the gene (PM6_Moderate, PMID: 1346349).
PS3_Moderate
The in-vitro expression of ADA activity in E. coli showed an expressed ADA Activity (Range) [nmol/h/mg protein]: 30.4 +- 35.8 (3.0–134.2), which means a Percent of Wild Type (Range) (Mean +- SD): 0.012 +- 0.014 (0.001–0.051); It belongs to Group I, indicating that the variant impacts the protein function. (PS3_Moderate; PMID 9758612).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 37/74910) of the c.986C>T variant in ADA is 0.0003683 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore do not meet this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.
PM3_Strong
This variant has been detected in many individuals in the literature. Evaluated here four patients with ADA-SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant: * PMID 8614422, compound heterozygous with p.Gly74Val (at least likely pathogenic according to SCID VCEP specifications, Phase is not confirmed = 0.25pt; * PMID 32307643, compound heterozygous with p.Ser291Leu (at least likely pathogenic according to SCID VCEP specifications. Phase is not confirmed = 0.25pt; * PMID: 8401541, Proband 1 is comp. het. A329V and Q254X (at least likely pathogenic according to SCID VCEP specifications - PM2_Supporting and PVS1) - phase (in trans) confirmed = 1pt; Additionally, 01 individual was homozygous for the variant = 0.5 pts (PMID: 1346349). The total is 2, PM3_Strong.
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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