Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8589684, 17181544, 25875700, 32307643, 33726816, 32098966, 31858364, 26255240)
ClinVar Genomic variation as it relates to human health
NM_000022.4(ADA):c.7C>T (p.Gln3Ter)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000022.4(ADA):c.7C>T (p.Gln3Ter)
Variation ID: 377441 Accession: VCV000377441.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.12 20: 44651601 (GRCh38) [ NCBI UCSC ] 20: 43280242 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 8, 2017 Oct 8, 2024 Jul 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000022.4:c.7C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000013.2:p.Gln3Ter nonsense NM_001322050.2:c.-283C>T 5 prime UTR NM_001322051.2:c.7C>T NP_001308980.1:p.Gln3Ter nonsense NR_136160.2:n.99C>T non-coding transcript variant NC_000020.11:g.44651601G>A NC_000020.10:g.43280242G>A NG_007385.1:g.5135C>T NG_046759.1:g.22698G>A LRG_16:g.5135C>T LRG_16t1:c.7C>T - Protein change
- Q3*
- Other names
- -
- Canonical SPDI
- NC_000020.11:44651600:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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 | |
| LOC107303343 | - | - | - | GRCh38 | - | 143 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 30, 2022 | RCV000433743.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 3, 2023 | RCV000687426.11 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jan 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928190.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
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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: SCV001977526.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Jul 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000511977.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8589684, 17181544, 25875700, 32307643, 33726816, 32098966, 31858364, 26255240) (less)
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Pathogenic
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
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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: SCV004213356.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 03, 2023)
|
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: SCV000814991.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln3*) in the ADA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln3*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8589684, 25875700, 25954555). ClinVar contains an entry for this variant (Variation ID: 377441). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 20, 2023)
|
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
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329554.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The observed stop gain variant c.7C>T (p.Gln3Ter) in ADA gene has been reported previously in homozygous state in multiple individuals affected with ADA related disorder … (more)
The observed stop gain variant c.7C>T (p.Gln3Ter) in ADA gene has been reported previously in homozygous state in multiple individuals affected with ADA related disorder (Pajno R, et al. 2020; Sanchez JJ et al. 2007). The p.Gln3Ter variant has allele frequency 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.7C>T in ADA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in ADA are known to be pathogenic (Baffelli R et al. 2015). For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the immune system (present)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln3*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8589684, 25875700, 25954555). ClinVar contains an entry for this variant (Variation ID: 377441). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed stop gain variant c.7C>T (p.Gln3Ter) in ADA gene has been reported previously in homozygous state in multiple individuals affected with ADA related disorder (Pajno R, et al. 2020; Sanchez JJ et al. 2007). The p.Gln3Ter variant has allele frequency 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.7C>T in ADA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in ADA are known to be pathogenic (Baffelli R et al. 2015). 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:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8589684, 17181544, 25875700, 32307643, 33726816, 32098966, 31858364, 26255240)
Comment:
This sequence change creates a premature translational stop signal (p.Gln3*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8589684, 25875700, 25954555). ClinVar contains an entry for this variant (Variation ID: 377441). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed stop gain variant c.7C>T (p.Gln3Ter) in ADA gene has been reported previously in homozygous state in multiple individuals affected with ADA related disorder (Pajno R, et al. 2020; Sanchez JJ et al. 2007). The p.Gln3Ter variant has allele frequency 0% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.7C>T in ADA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in ADA are known to be pathogenic (Baffelli R et al. 2015). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Adenosine deaminase deficient severe combined immunodeficiency presenting as atypical haemolytic uraemic syndrome. | Nikolajeva O | Journal of clinical immunology | 2015 | PMID: 25875700 |
| Atypical Omenn Syndrome due to Adenosine Deaminase Deficiency. | Joshi AY | Case reports in immunology | 2012 | PMID: 25954555 |
| Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA. | Santisteban I | Human molecular genetics | 1995 | PMID: 8589684 |
Text-mined citations for rs1057520217 ...
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 Oct 08, 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.