NM_000022.4(ADA):c.704G>A (p.Arg235Gln) AND Severe combined immunodeficiency due to ADA deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 10, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000215113.6

Allele description [Variation Report for NM_000022.4(ADA):c.704G>A (p.Arg235Gln)]

NM_000022.4(ADA):c.704G>A (p.Arg235Gln)

Gene:
ADA:adenosine deaminase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.12
Genomic location:
Preferred name:
NM_000022.4(ADA):c.704G>A (p.Arg235Gln)
HGVS:
  • NC_000020.11:g.44622905C>T
  • NG_007385.1:g.33831G>A
  • NM_000022.4:c.704G>AMANE SELECT
  • NM_001322050.2:c.299G>A
  • NM_001322051.2:c.632G>A
  • NP_000013.2:p.Arg235Gln
  • NP_001308979.1:p.Arg100Gln
  • NP_001308980.1:p.Arg211Gln
  • LRG_16t1:c.704G>A
  • LRG_16:g.33831G>A
  • NC_000020.10:g.43251546C>T
  • NM_000022.2:c.704G>A
  • NR_136160.2:n.796G>A
Protein change:
R100Q
Links:
dbSNP: rs79281338
NCBI 1000 Genomes Browser:
rs79281338
Molecular consequence:
  • NM_000022.4:c.704G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322050.2:c.299G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322051.2:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136160.2:n.796G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Severe combined immunodeficiency due to ADA deficiency
Synonyms:
ADA-SCID; SCID DUE TO ADA DEFICIENCY, EARLY-ONSET; ADA deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007064; MedGen: C1863236; Orphanet: 277; OMIM: 102700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000271204Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Nov 9, 2015)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000794032Counsylcriteria provided, single submitter
Likely pathogenic
(Sep 6, 2017)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000813414Invitaecriteria provided, single submitter
Pathogenic
(May 4, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001977498Nilou-Genome Labcriteria provided, single submitter
Likely pathogenic
(Aug 10, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided21not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genotype is an important determinant of phenotype in adenosine deaminase deficiency.

Hershfield MS.

Curr Opin Immunol. 2003 Oct;15(5):571-7. Review.

PubMed [citation]
PMID:
14499267

Determination of adenosine deaminase activity in dried blood spots by a nonradiochemical assay using reversed-phase high-performance liquid chromatography.

van Kuilenburg AB, Zoetekouw L, Meijer J, Kuijpers TW.

Nucleosides Nucleotides Nucleic Acids. 2010 Jun;29(4-6):461-5. doi: 10.1080/15257771003741406.

PubMed [citation]
PMID:
20544538
See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000271204.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (6)

Description

The p.Arg235Gln variant in ADA has been reported in 3 individuals with SCID due to adenosine deaminase deficiency, confirmed by decreased ADA enzyme activity in patient cells (Ariga 2001a, Baffelli 2015). All of these individuals were compo und heterozygous and two of them had a second ADA variant predicted to cause los s of function of the gene on the other allele. The p.Arg235Gln variant was absen t from large population studies. Computational prediction tools and conservation analyses suggest that the variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. Furthermore, in vitro fu nctional studies provide some evidence that this variant impacts protein functio n (Ariga 2001b), although these types of assays may not accurately represent bio logical function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided1not provided

From Counsyl, SCV000794032.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000813414.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with glutamine at codon 235 of the ADA protein (p.Arg235Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with other ADA variants in several individuals affected with adenosine deaminase deficiency (PMID: 11313286, 26376800). In two individuals with ADA enzyme deficiency, this variant was observed on the opposite chromosome (in trans) from another pathogenic ADA variant (PMID: 11313286). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 228244). Experimental studies have shown that this missense change impairs ADA enzyme activity in vitro (PMID: 11160213). The p.Arg235Trp amino acid residue in ADA has been determined to be clinically significant (PMID: 21624848, 26255240, 26376800, Invitae). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Nilou-Genome Lab, SCV001977498.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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