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.646G>A (p.Gly216Arg)

CA252008

1968 (ClinVar)

Gene: ADA
Condition: adenosine deaminase deficiency
Inheritance Mode: Autosomal recessive inheritance
UUID: a0ddb75c-ba0b-4900-89fd-00d467cb01d7
Approved on: 2024-01-24
Published on: 2024-01-24

HGVS expressions

NM_000022.4:c.646G>A
NM_000022.4(ADA):c.646G>A (p.Gly216Arg)
NC_000020.11:g.44623039C>T
CM000682.2:g.44623039C>T
NC_000020.10:g.43251680C>T
CM000682.1:g.43251680C>T
NC_000020.9:g.42685094C>T
NG_007385.1:g.33697G>A
ENST00000372874.9:c.646G>A
ENST00000372874.8:c.646G>A
ENST00000372887.5:c.152-894C>T
ENST00000464097.5:n.320G>A
ENST00000492931.5:n.730G>A
ENST00000536532.5:c.646G>A
ENST00000537820.1:c.607-109G>A
ENST00000539235.5:c.*30G>A
NM_000022.2:c.646G>A
NM_000022.3:c.646G>A
NM_001322050.1:c.241G>A
NM_001322051.1:c.607-109G>A
NR_136160.1:n.797G>A
NM_001322050.2:c.241G>A
NM_001322051.2:c.607-109G>A
NR_136160.2:n.738G>A
More

Pathogenic

Met criteria codes 5
PP1_Strong PM3_Strong PM2_Supporting PS3_Moderate PP4_Moderate
Not Met criteria codes 6
PS4 PP3 PP2 PM1 BP4 BP1

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
NM_000022.4 :c.646G>A is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 216 (p.Gly216Arg). The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240). This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt.). 12 individuals were homozygous for the variant (1 pt.) (total: 2 pts; PM3_Strong ,PMID : 26255240). Male patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt.),Increased dATP in pretreatment erythrocytes (2 pts.). (PP4_Moderate (5 pts.), PMID: 1680289). ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate). Based on the above evidence, the variant may be classified as pathogenic for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_strong,PM2_supporting,PM3_strong,PP4_moderate,PS3_moderate (VCEP specifications version 1).
Met criteria codes
PP1_Strong
The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240)
PM3_Strong
This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt). 12 individuals were homozygous for the variant (1 pt) (total: 2 pts; PM3_Strong ,PMID : 26255240).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
PS3_Moderate
ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate).
PP4_Moderate
Male patient with SCID (0.5 pt), genome sequencing conducted (0.5 pt), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt),Increased dATP in pretreatment erythrocytes (2 pts). (PP4_Moderate (5 pts), PMID: 1680289)
Not Met criteria codes
PS4
Does not apply.
PP3
Does not apply.
PP2
Does not apply.
PM1
Does not apply.
BP4
Does not apply.
BP1
Does not apply.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.