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]

Variant: NM_000022.4(ADA):c.454C>A (p.Leu152Met)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA115292

1979 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9de80e0f-5b92-4026-b56c-a0636992c669

Approved on: 2024-01-16

Published on: 2024-01-16

HGVS expressions

NM_000022.4:c.454C>A

NM_000022.4(ADA):c.454C>A (p.Leu152Met)

NC_000020.11:g.44625593G>T

CM000682.2:g.44625593G>T

NC_000020.10:g.43254234G>T

CM000682.1:g.43254234G>T

NC_000020.9:g.42687648G>T

NG_007385.1:g.31143C>A

ENST00000372874.9:c.454C>A

ENST00000372874.8:c.454C>A

ENST00000464097.5:n.128C>A

ENST00000492931.5:n.538C>A

ENST00000536532.5:c.454C>A

ENST00000537820.1:c.454C>A

ENST00000539235.5:c.219-2515C>A

NM_000022.2:c.454C>A

NM_000022.3:c.454C>A

NM_001322050.1:c.73+863C>A

NM_001322051.1:c.454C>A

NR_136160.1:n.605C>A

NM_001322050.2:c.73+863C>A

NM_001322051.2:c.454C>A

NR_136160.2:n.546C>A

Uncertain Significance

PP4_Moderate PP1

PS3 PM2 PM5 PM3 BS1

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.454C>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Leu by Met at amino acid 152. The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742). So, PM2 is not met. The variant has been reported to segregate with SCID in 02 affected members (proband +1) from one family. LOD score: 0.6 = PP1_supporting. At least one patient (P6, PMID: 29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point, and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID: 29744787.) In summary, this variant meets the criteria to be classified as VUS for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP1_Supporting, PP4_Moderate (SCID VCEP specifications version 1.0).

PP4_Moderate

At least one patient (P6, PMID: 29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID: 29744787.)

PP1

PMID: 29744787: two siblings compound heterozygous for p.L152M and p.R235Q. Siblings are similarly affected. 1 affected segregation. LOD score 0.6, qualifies for PP1 at supporting level.

PS3

Despite this paper (PMID: 9225964) reporting that p.Leu152Met shows activity equal to 1.5% of wild type, it was done using transfected COS cells instead of E. coli (used in Arredondo-Vega 1998). So, we cannot compare our thresholds with this paper. Thus, PS3 is not met.

PM2

The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742), so PM2 is not met.

PM5

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

PM3

Despite the fact that both patients (P6 and P7 PMID: 29744787) had a second variant (c.704G>A R235Q, unknown phase), the code does not apply because the assessed variant does not meet PM2 threshold.

BS1

SCID VCEP specification for BS1 are gnomAD popmax filtering allele frequency > 0.00161 for ADA and all allele frequencies (overall and all subpopulations) in gnomAD are below this, so BS1 is not met.

Curation History

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