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]

Variant: NM_000022.4(ADA):c.532del (p.Val177_Val178insTer)

CA636174167

505549 (ClinVar)

Gene: ADA
Condition: adenosine deaminase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 9e3329c3-f068-4560-a527-446480aa9df4
Approved on: 2024-01-16
Published on: 2024-01-16

HGVS expressions

NM_000022.4:c.532del
NM_000022.4(ADA):c.532del (p.Val177_Val178insTer)
NC_000020.11:g.44624277del
CM000682.2:g.44624277del
NC_000020.10:g.43252918del
CM000682.1:g.43252918del
NC_000020.9:g.42686332del
NG_007385.1:g.32460del
ENST00000372874.9:c.532del
ENST00000372874.8:c.532del
ENST00000464097.5:n.206del
ENST00000492931.5:n.616del
ENST00000536532.5:c.532del
ENST00000537820.1:c.532del
ENST00000539235.5:c.219-1198del
NM_000022.2:c.532del
NM_000022.3:c.532del
NM_001322050.1:c.127del
NM_001322051.1:c.532del
NR_136160.1:n.683del
NM_001322050.2:c.127del
NM_001322051.2:c.532del
NR_136160.2:n.624del
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Pathogenic

Met criteria codes 4
PP4 PVS1 PM3_Supporting PM2_Supporting

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 NM_000022.4:c.532del (p.Val178*) variant in ADA creates a premature translational stop signal in exon 6 (of 12) and is expected to result in nonsense-mediated decay in a loss of function gene (PVS1). This variant was reported as homozygous in an infant with T-B- severe combined immunodeficiency (SCID) (PMID: 30290665) (PP4, PM3_Supporting). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.0001 (2/19948 alleles) in the East Asian population, which is lower than the ADA cutoff (gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. 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, PP4, PM3_Supporting, PM2_Supporting (SCID VCEP specifications version 1.0).
Met criteria codes
PP4
Identified 1 homozygous proband with clinical diagnosis of SCID (T-B-)= 0.5p. A large SCID panel was tested, so it also meets PP4 specification for "SCID gene panel or exome/genome sequencing conducted (only applicable if genetic testing did not provide an alternative genetic explanation for SCID/Leaky SCID/Omenn syndrome phenotype)" = 0.5p. NK cells were not mentioned, but given the gene panel or exome/genome sequencing had ruled out alternative causes, we can apply T-B-NK- lymphocyte subset profile = 0.5p. Total 0.5p + 0.5p + 0.5p = 1.5 pts, PP4 is met.
PVS1
Nonsense variant occurring in exon 6 (of 12). NMD+ variant in a loss of function gene.
PM3_Supporting
Homozygous in 1 proband meeting PP4 criteria. 1 homozygous occurrence is worth 0.5p which allows for PM3 at supporting level.
PM2_Supporting
Overall 2/282722 alleles in gnomAD v.2.1.1 (0.000007074). No homozygotes. https://gnomad.broadinstitute.org/variant/20-43252916-AC-A. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.0001 (2/19948 alleles) in the East Asian population, which is lower than the ADA cutoff (gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met.
Curation History
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