Variant: NM_000022.4(ADA):c.396dup (p.Val133fs)

CA658824668

550821 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 4ab2445c-e8c4-479d-87cb-de2f90731ef3

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000022.4:c.396dup
NM_000022.4(ADA):c.396dup (p.Val133fs)
NC_000020.11:g.44625651dup
CM000682.2:g.44625651dup
NC_000020.10:g.43254292dup
CM000682.1:g.43254292dup
NC_000020.9:g.42687706dup
NG_007385.1:g.31085dup
ENST00000372874.9:c.396dup
ENST00000372874.8:c.396dup
ENST00000464097.5:n.70dup
ENST00000492931.5:n.480dup
ENST00000536532.5:c.396dup
ENST00000537820.1:c.396dup
ENST00000539235.5:c.219-2573dup
NM_000022.2:c.396dup
NM_000022.3:c.396dup
NM_001322050.1:c.73+805dup
NM_001322051.1:c.396dup
NR_136160.1:n.547dup
NM_001322050.2:c.73+805dup
NM_001322051.2:c.396dup
NR_136160.2:n.488dup

Pathogenic

• Met criteria codes: PVS1 PP4 PM2_Supporting

• Not Met criteria codes: PM3

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

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID: 21664875). 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: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1).

Met criteria codes

• PVS1: The c.396dup (p.Val133Serfs*38) (NM_000022.4) variant in ADA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: At least one patient with this variant displayed Diagnostic criteria for Leaky SCID (0.5pt) + T-B-NK- lymphocyte subset profile (0.5pt) = 1 point TOTAL, which is highly specific for SCID (PP4_Met, PMID: 21664875).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PM3: PMID 21664875, patient #69: The patient was diagnosed with atypical SCID. The patient was compound heterozygous with another variant not yet curated by the SCID VCEP (c.780+1G>A: This variant will not be evaluated now because the pathogenic level was already reached.)