NM_000022.4(ADA):c.631C>T (p.Arg211Cys) AND Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Germline classification:: Likely pathogenic (9 submissions)
Last evaluated:: Jan 10, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000059111.20

Allele description [Variation Report for NM_000022.4(ADA):c.631C>T (p.Arg211Cys)]

NM_000022.4(ADA):c.631C>T (p.Arg211Cys)

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.631C>T (p.Arg211Cys)

Other names:

NM_000022.4(ADA):c.631C>T

HGVS:

NC_000020.11:g.44623054G>A
NG_007385.1:g.33682C>T
NM_000022.4:c.631C>TMANE SELECT
NM_001322050.2:c.226C>T
NM_001322051.2:c.607-124C>T
NP_000013.2:p.Arg211Cys
NP_001308979.1:p.Arg76Cys
LRG_16t1:c.631C>T
LRG_16:g.33682C>T
NC_000020.10:g.43251695G>A
NM_000022.2:c.631C>T
NM_000022.3:c.631C>T
NR_136160.2:n.723C>T
P00813:p.Arg211Cys

Protein change:

R211C; ARG211CYS

Links:

UniProtKB: P00813#VAR_002231; UniProtKB/Swiss-Prot: VAR_002231; OMIM: 608958.0014; dbSNP: rs121908740

NCBI 1000 Genomes Browser:

rs121908740

Molecular consequence:

NM_001322051.2:c.607-124C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000022.4:c.631C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322050.2:c.226C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136160.2:n.723C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000090636	UniProtKB/Swiss-Prot	no classification provided	not provided	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000915942	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Nov 1, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 2166947, 8051429, 9361033, 9758612, 3182793 Citation Link,
SCV000931469	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 2166947, 8051429, 9616253, 9361033, 1974554, 9414266, 9758612, 26376800, 28492532
SCV001461843	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001977337	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004216726	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242244	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications ADA V1.0.0)	Likely pathogenic (Jan 10, 2024)	germline	curation	Citation Link,
SCV005051777	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts.

Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ.

J Biol Chem. 1988 Nov 5;263(31):16291-6.

PubMed [citation]

PMID:: 3182793

Hot spot mutations in adenosine deaminase deficiency.

Hirschhorn R, Tzall S, Ellenbogen A.

Proc Natl Acad Sci U S A. 1990 Aug;87(16):6171-5.

PubMed [citation]

PMID:: 2166947
PMCID:: PMC54494

See all PubMed Citations (11)

Details of each submission

From UniProtKB/Swiss-Prot, SCV000090636.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000799872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915942.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The ADA c.631C>T (p.Arg211Cys) variant was first reported by Hirschhorn et al. (1990) in a child with partial adenosine deaminase (ADA) deficiency. This patient was compound heterozygous for p.Arg211Cys and a second missense variant, and had approximately 8% residual ADA activity in lymphoid cells. The p.Arg211Cys variant was subsequently identified in a compound heterozygous state with a second deletion variant in two siblings with ADA deficiency and combined immunodeficiency, with no detectable ADA activity. The p.Arg211Cys variant was also detected in a heterozygous state in the mother, two additional siblings, and in a patient's child, all of whom had normal or below normal ADA activity (Shovlin et al. 1994). Control data are unavailable for this variant, but it is reported at a frequency of 0.00078 in the Latino population of the Exome Aggregation Consortium. Expression studies in COS cells by Jiang et al. (1997) showed that the p.Arg211Cys variant resulted in residual ADA activity of approximately 4% of normal. Another variant at this position, p.Arg211His, has also been seen in patients with ADA deficiency (Akeson et al. 1988; Arredondo-Vega et al. 1998). Based on the collective evidence, the p.Arg211Cys variant is classified as likely pathogenic for adenosine deaminase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000931469.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the ADA protein (p.Arg211Cys). This variant is present in population databases (rs121908740, gnomAD 0.07%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 2166947, 8051429, 9616253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1966). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9361033, 9758612). This variant disrupts the p.Arg211 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1974554, 9414266, 9758612, 26376800). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461843.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001977337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004216726.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004242244.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID: 2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant 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_moderate,PM3,PM5(VCEP specifications version 1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799872	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 10, 2018)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2166947, 9758612, 9361033, 8051429 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000799872

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(May 10, 2018)

unknown

clinical testing

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

Citation Link

Last Updated: Sep 29, 2024

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