VCV000001962.24 - ClinVar

NM_000022.4(ADA):c.226C>T (p.Arg76Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000022.4(ADA):c.226C>T (p.Arg76Trp)

Variation ID: 1962 Accession: VCV000001962.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44626592 (GRCh38) [ NCBI UCSC ] 20: 43255233 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000022.4:c.226C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000013.2:p.Arg76Trp	missense
NM_001322050.2:c.-64C>T		5 prime UTR
NM_001322051.2:c.226C>T	NP_001308980.1:p.Arg76Trp	missense
NR_136160.2:n.318C>T		non-coding transcript variant
NC_000020.11:g.44626592G>A
NC_000020.10:g.43255233G>A
NG_007385.1:g.30144C>T
LRG_16:g.30144C>T
LRG_16t1:c.226C>T
	P00813:p.Arg76Trp

... more HGVS ... less HGVS

Protein change

R76W

Other names

Canonical SPDI

NC_000020.11:44626591:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00180 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00028

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD) 0.00081

Trans-Omics for Precision Medicine (TOPMed) 0.00089

1000 Genomes Project 30x 0.00141

1000 Genomes Project 0.00180

Links

ClinGen: CA115279 UniProtKB: P00813#VAR_002213 UniProtKB/Swiss-Prot: VAR_002213 OMIM: 608958.0010 dbSNP: rs121908736 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ADA		-	-	GRCh38 GRCh37	531	685

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Partial adenosine deaminase deficiency	Pathogenic (1)	no assertion criteria provided	Aug 1, 1990	RCV000002039.2
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Oct 24, 2022	RCV000059096.14
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000482569.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001419110.2 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 2166947 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the ADA protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the ADA protein (p.Arg76Trp). This variant is present in population databases (rs121908736, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with partial adenosine deaminase deficiency (PMID: 2166947). ClinVar contains an entry for this variant (Variation ID: 1962). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005194992.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004811731.7 First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024	Comment: ADA: PS3:Supporting Number of individuals with the variant: 1
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001303124.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 2166947 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002027196.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Uncertain significance (Dec 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568505.5 First in ClinVar: Apr 29, 2017 Last updated: Jul 23, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28471432, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28471432, 9225964, 35914665, 21228398, 1346349, 8433873, 2166947) (less)
Pathogenic (Aug 01, 1990)	no assertion criteria provided Method: literature only	ADENOSINE DEAMINASE DEFICIENCY, PARTIAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022197.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 2166947 Comment on evidence: In 3 patients with partial ADA deficiency who lacked ADA activity in erythrocytes but retained ADA activity in lymphocytes (102700), Hirschhorn et al. (1990) identified … (more) In 3 patients with partial ADA deficiency who lacked ADA activity in erythrocytes but retained ADA activity in lymphocytes (102700), Hirschhorn et al. (1990) identified a 226C-T transition in exon 4 of the ADA gene, resulting in an arg76-to-trp (R76W) substitution. The R76W mutant allele resulted in an abnormally acidic protein with 16% normal activity in lymphoid cells. One patient was homozygous and the other 2 were compound heterozygous (see also 608958.0012 and 608958.0013). All 3 patients were from the West Indies, and the authors postulated a selective advantage of carrying a mutant allele for partial ADA deficiency. (less)
Uncertain significance (Oct 20, 2020)	no assertion criteria provided Method: clinical testing	Severe combined immunodeficiency due to ADA deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002095332.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: not provided	Severe combined immunodeficiency due to ADA deficiency Affected status: not provided Allele origin: unknown	UniProtKB/Swiss-Prot Accession: SCV000090617.1 First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the ADA protein (p.Arg76Trp). This variant is present in population databases (rs121908736, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with partial adenosine deaminase deficiency (PMID: 2166947). ClinVar contains an entry for this variant (Variation ID: 1962). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28471432, 9225964, 35914665, 21228398, 1346349, 8433873, 2166947)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hot spot mutations in adenosine deaminase deficiency.	Hirschhorn R	Proceedings of the National Academy of Sciences of the United States of America	1990	PMID: 2166947

Text-mined citations for rs121908736 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000022.4(ADA):c.226C>T (p.Arg76Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908736 ...