NM_000022.4(ADA):c.529G>A (p.Val177Met) AND Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000059107.11

Allele description [Variation Report for NM_000022.4(ADA):c.529G>A (p.Val177Met)]

NM_000022.4(ADA):c.529G>A (p.Val177Met)

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.529G>A (p.Val177Met)

HGVS:

NC_000020.11:g.44624279C>T
NG_007385.1:g.32457G>A
NM_000022.4:c.529G>AMANE SELECT
NM_001322050.2:c.124G>A
NM_001322051.2:c.529G>A
NP_000013.2:p.Val177Met
NP_001308979.1:p.Val42Met
NP_001308980.1:p.Val177Met
LRG_16t1:c.529G>A
LRG_16:g.32457G>A
NC_000020.10:g.43252920C>T
NM_000022.2:c.529G>A
NR_136160.2:n.621G>A
P00813:p.Val177Met

Protein change:

V177M

Links:

UniProtKB: P00813#VAR_002228; UniProtKB/Swiss-Prot: VAR_002228; dbSNP: rs121908719

NCBI 1000 Genomes Browser:

rs121908719

Molecular consequence:

NM_000022.4:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322050.2:c.124G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322051.2:c.529G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136160.2:n.621G>A - 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
SCV000090632	UniProtKB/Swiss-Prot	no classification provided	not provided	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000798724	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 23, 2018)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22447032, 9758612, 19665771, 26376800, 8227344 Citation Link,
SCV000941432	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8227344, 26376800, 9758612, 28492532
SCV001461846	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001977508	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]
SCV004216659	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis.

Nakaoka H, Kanegane H, Taneichi H, Miya K, Yang X, Nomura K, Takezaki S, Yamada M, Ohara O, Kamae C, Imai K, Nonoyama S, Wada T, Yachie A, Hershfield MS, Ariga T, Miyawaki T.

Int J Hematol. 2012 Jun;95(6):692-6. doi: 10.1007/s12185-012-1055-4. Epub 2012 Mar 24.

PubMed [citation]

PMID:: 22447032

Polyethylene glycol-modified adenosine deaminase improved lung disease but not liver disease in partial adenosine deaminase deficiency.

Somech R, Lai YH, Grunebaum E, Le Saux N, Cutz E, Roifman CM.

J Allergy Clin Immunol. 2009 Oct;124(4):848-50. doi: 10.1016/j.jaci.2009.07.003. Epub 2009 Aug 8. No abstract available.

PubMed [citation]

PMID:: 19665771

See all PubMed Citations (7)

Details of each submission

From UniProtKB/Swiss-Prot, SCV000090632.1

#	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, SCV000798724.1

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

#	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 Invitae, SCV000941432.6

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 177 of the ADA protein (p.Val177Met). This variant is present in population databases (rs121908719, gnomAD 0.006%). This missense change has been observed in individual(s) with ADA-SCID (PMID: 8227344, 26376800). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68265). 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 expected to disrupt ADA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). 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., SCV001461846.1

#	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, SCV001977508.1

#	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, SCV004216659.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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