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.703C>T (p.Arg235Trp)

CA9871550

468281 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ff38cc3b-e966-4c99-ab3c-49f5c18a6446

Approved on: 2024-01-16

Published on: 2024-01-16

HGVS expressions

NM_000022.4:c.703C>T

NM_000022.4(ADA):c.703C>T (p.Arg235Trp)

NC_000020.11:g.44622906G>A

CM000682.2:g.44622906G>A

NC_000020.10:g.43251547G>A

CM000682.1:g.43251547G>A

NC_000020.9:g.42684961G>A

NG_007385.1:g.33830C>T

ENST00000372874.9:c.703C>T

ENST00000372874.8:c.703C>T

ENST00000372887.5:c.152-1027G>A

ENST00000464097.5:n.453C>T

ENST00000492931.5:n.863C>T

ENST00000536532.5:c.703C>T

ENST00000537820.1:c.631C>T

ENST00000539235.5:c.*87C>T

NM_000022.2:c.703C>T

NM_000022.3:c.703C>T

NM_001322050.1:c.298C>T

NM_001322051.1:c.631C>T

NR_136160.1:n.854C>T

NM_001322050.2:c.298C>T

NM_001322051.2:c.631C>T

NR_136160.2:n.795C>T

Likely Pathogenic

PM3_Strong PM5_Supporting PM2_Supporting PP4

BS3 PS2 PS3 PS1 PP1 PM6

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.703C>T (NM_000022.4) variant in ADA gene is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 235 (p.Arg235Trp). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt). Total = 3 pts, PM3_Strong. Evaluating those 5 probands, three of them had PP4 applied at supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt = TOTAL: 1.5 pts = PP4_Met. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PP4, PM3_Strong, and PM5_supporting. (VCEP specifications version 1).

PM3_Strong

This variant has been detected in at least 5 individuals with SCID. Of those individuals, 2 were compound heterozygous: Patient #6, W264X, reported by Dalal I et al. (PMID: 21624848, Pathogenic according to the SCID VCEP specifications, confirmed in trans, 1pt) and Patient #26, p.G74D, reported by Chi ZH et al. (PMID: 30290665, Likey Pathogenic according to the SCID VCEP, confirmed in trans, 1 pt). 3 individuals were homozygous for PMIDs: 26255240, 26376800, and 32307643; reaching the limit for homozygous occurrence = 1 pt) Total = 3 pts, PM3_Strong.

PM5_Supporting

There is another missense variant reported in the same codon on ClinVar: NM_000022.4(ADA):c.704G>A (p.Arg235Gln); LP according to the SCID VCEP specifications. PM5_Supporting.

PM2_Supporting

The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/113770 observed alleles) is 0.000002920 in gnomAD v2.1.1 which is below than SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting).

PP4

At least five probands have been reported in the literature with this variant. At least three of them reached PP4 at the supporting level: * PMID: 30290665: 171 PID-related genes(NGS panel: 0.5pt); T-B-SCID ( SCID gene panel which ruled out alternative causes 0.5pt); SCID diagnostic (0.5pt); Total 1.5pts. * PMID: 26376800: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts, PP4_Met. * PMID: 26255240: Diagnostic criteria for SCID: 0,5 pt + Reduced ADA enzyme activity in patient cells: 1pt. TOTAL: 1.5 pts = PP4_Met.

BS3