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.632G>A (p.Arg211His)

CA252000

1957 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4c664ec8-5d63-46a5-a3d1-142655c6aa1c

HGVS expressions

NM_000022.4:c.632G>A

NM_000022.4(ADA):c.632G>A (p.Arg211His)

NC_000020.11:g.44623053C>T

CM000682.2:g.44623053C>T

NC_000020.10:g.43251694C>T

CM000682.1:g.43251694C>T

NC_000020.9:g.42685108C>T

NG_007385.1:g.33683G>A

ENST00000372874.9:c.632G>A

ENST00000372874.8:c.632G>A

ENST00000372887.5:c.152-880C>T

ENST00000464097.5:n.306G>A

ENST00000492931.5:n.716G>A

ENST00000536532.5:c.632G>A

ENST00000537820.1:c.607-123G>A

ENST00000539235.5:c.*16G>A

NM_000022.2:c.632G>A

NM_000022.3:c.632G>A

NM_001322050.1:c.227G>A

NM_001322051.1:c.607-123G>A

NR_136160.1:n.783G>A

NM_001322050.2:c.227G>A

NM_001322051.2:c.607-123G>A

NR_136160.2:n.724G>A

Pathogenic

PM2 PP4_Moderate PP1_Strong PM3_Strong PS3_Moderate

PS1

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.632G>A variant in ADA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 211 (p.Arg211His). The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID: 9758612, PS3_moderate). This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID: 9414266). The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Moderate, PM3_Strong, PP1_Strong, PM2_Supporting, PS3_Moderate. (VCEP specifications version 1).

PM2

The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting).

PP4_Moderate

At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID: 9414266).

PP1_Strong

The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800).

PM3_Strong

This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met.

PS3_Moderate

Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID: 9758612, PS3_moderate).

PS1

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

Approved on: 2024-01-17

Published on: 2024-01-17

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