Variant summary: ADA c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 29856 control chromosomes. c.466C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome. These data indicate that the variant is very likely to be associated with disease. The variant has been reported to have <10% wild-type enzymatic activity in cells expressing recombinant protein (Arredondo-Vega_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000022.4(ADA):c.466C>T (p.Arg156Cys)
Germline
Classification
Help
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)
Help
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.
Pathogenic/Likely pathogenic
9
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.466C>T (p.Arg156Cys)
Variation ID: 1970 Accession: VCV000001970.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.12 20: 44625581 (GRCh38) [ NCBI UCSC ] 20: 43254222 (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 Jun 17, 2024 Feb 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000022.4:c.466C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000013.2:p.Arg156Cys missense NM_001322050.2:c.73+875C>T intron variant NM_001322051.2:c.466C>T NP_001308980.1:p.Arg156Cys missense NR_136160.2:n.558C>T non-coding transcript variant NC_000020.11:g.44625581G>A NC_000020.10:g.43254222G>A NG_007385.1:g.31155C>T LRG_16:g.31155C>T LRG_16t1:c.466C>T P00813:p.Arg156Cys - Protein change
- R156C
- Other names
- -
- Canonical SPDI
- NC_000020.11:44625580:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00010
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2024 | RCV000002047.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 2, 2018 | RCV000780816.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 19, 2021 | RCV001588796.3 |
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. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(May 12, 2017)
|
criteria provided, single submitter
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:
unknown
|
Counsyl
Accession: SCV000791548.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Aug 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Severe combined immunodeficiency disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918390.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ADA c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain of the encoded protein sequence. Four of … (more)
Variant summary: ADA c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 29856 control chromosomes. c.466C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome. These data indicate that the variant is very likely to be associated with disease. The variant has been reported to have <10% wild-type enzymatic activity in cells expressing recombinant protein (Arredondo-Vega_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001814992.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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: 1284479, … (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: 1284479, 33628209, 31858364, 32888943, 32307643, 22447032, 21228398, 9758612, 26376800, 26255240, 27129325) (less)
|
|
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Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
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: SCV001232172.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the ADA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the ADA protein (p.Arg156Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ADA-related conditions (PMID: 1284479, 9758612, 22447032, 26376800). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1970). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
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: SCV001977511.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Pathogenic
(Feb 09, 2024)
|
criteria provided, single submitter
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:
unknown
|
Baylor Genetics
Accession: SCV004215212.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 01, 1992)
|
no assertion criteria provided
Method: literature only
|
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022205.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with SCID due to ADA deficiency (102700) who was unusual for responding to the limited form of enzyme therapy provided by repeated … (more)
In a patient with SCID due to ADA deficiency (102700) who was unusual for responding to the limited form of enzyme therapy provided by repeated partial exchange transfusions (Polmar et al., 1976; Dyminski et al., 1979), Hirschhorn (1992) identified compound heterozygosity for 2 mutations in the ADA gene: a 466C-T transition, resulting in an arg156-to-cys (R156C) substitution and L304R (608958.0005). (less)
|
|
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Severe combined immunodeficiency due to ADA deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461847.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
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: SCV000090630.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013 |
|
Comment:
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: 1284479, 33628209, 31858364, 32888943, 32307643, 22447032, 21228398, 9758612, 26376800, 26255240, 27129325)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the ADA protein (p.Arg156Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ADA-related conditions (PMID: 1284479, 9758612, 22447032, 26376800). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1970). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
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:
Variant summary: ADA c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 29856 control chromosomes. c.466C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome. These data indicate that the variant is very likely to be associated with disease. The variant has been reported to have <10% wild-type enzymatic activity in cells expressing recombinant protein (Arredondo-Vega_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
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: 1284479, 33628209, 31858364, 32888943, 32307643, 22447032, 21228398, 9758612, 26376800, 26255240, 27129325)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the ADA protein (p.Arg156Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ADA-related conditions (PMID: 1284479, 9758612, 22447032, 26376800). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1970). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. | Cicalese MP | Blood | 2016 | PMID: 27129325 |
| Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience. | Baffelli R | Journal of clinical immunology | 2015 | PMID: 26376800 |
| Spectrum of mutations in a cohort of UK patients with ADA deficient SCID: Segregation of genotypes with specific ethnicities. | Adams SP | Clinical immunology (Orlando, Fla.) | 2015 | PMID: 26255240 |
| Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis. | Nakaoka H | International journal of hematology | 2012 | PMID: 22447032 |
| Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. | Arredondo-Vega FX | American journal of human genetics | 1998 | PMID: 9758612 |
| Identification of two new missense mutations (R156C and S291L) in two ADA- SCID patients unusual for response to therapy with partial exchange transfusions. | Hirschhorn R | Human mutation | 1992 | PMID: 1284479 |
| Immunological and biochemical profiles in response to transfusion therapy in an adenosine deaminase-deficient patient with severe combined immunodeficiency disease. | Dyminski JW | Clinical immunology and immunopathology | 1979 | PMID: 498598 |
| Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency. | Polmar SH | The New England journal of medicine | 1976 | PMID: 980079 |
Text-mined citations for rs121908735 ...
HelpThese 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 Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.