ClinVar Genomic variation as it relates to human health
NM_012452.3(TNFRSF13B):c.542C>A (p.Ala181Glu)
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.
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(7); Likely pathogenic(9); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012452.3(TNFRSF13B):c.542C>A (p.Ala181Glu)
Variation ID: 5303 Accession: VCV000005303.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p11.2 17: 16940415 (GRCh38) [ NCBI UCSC ] 17: 16843729 (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 Apr 4, 2013 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012452.3:c.542C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036584.1:p.Ala181Glu missense NC_000017.11:g.16940415G>T NC_000017.10:g.16843729G>T NG_007281.1:g.36674C>A LRG_120:g.36674C>A LRG_120t1:c.542C>A LRG_120p1:p.Ala181Glu - Protein change
- A181E
- Other names
- -
- Canonical SPDI
- NC_000017.11:16940414:G:T
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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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0.00160 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00156
1000 Genomes Project 0.00160
Trans-Omics for Precision Medicine (TOPMed) 0.00338
The Genome Aggregation Database (gnomAD) 0.00518
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 | ||
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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. |
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TNFRSF13B | - | - |
GRCh38 GRCh37 |
330 | 435 |
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. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000005625.21 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2020 | RCV000005626.9 | |
Conflicting interpretations of pathogenicity (11) |
criteria provided, conflicting classifications
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Mar 1, 2024 | RCV000255118.43 | |
Pathogenic (1) |
criteria provided, conflicting classifications
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May 1, 2019 | RCV000999848.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2020 | RCV001199863.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2022 | RCV002054419.5 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2020 | RCV002251881.5 |
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
(Jan 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000597507.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Likely pathogenic
(May 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Common variable agammaglobulinemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370599.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: TNFRSF13B c.542C>A (p.Ala181Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: TNFRSF13B c.542C>A (p.Ala181Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 250818 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 1864 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), suggesting that the variant is benign. However, this variant has been reported in many individuals with Common Variable Immunodeficiency (CVID, examples: Dong_2010, Castigli_2005, Martinez-Gallo_2013, Salzer_2011, Pomar_2009). These data indicate that the variant is likely to be associated with disease. The variant has been reported in CVID patients as heterozygous, homozygous, and in compound heterozygosity with other pathogenic variants in TNFRSF13B. c.542C>A has been shown to segregate with disease in multiple families (example: Castigli_2005), but has also been observed in unaffected family members (example: Martinez-Gallo_2013), indicating reduced penetrance. Different clinical manifestations have been observed in individuals with the variant, even within the same family (example: Dong_2010). The variant was associated with CVID in a case-control study (OR=5.60, CI 2.99-10.51; Pan-Hammarstrom_2007) and a meta-analysis of cases and controls from the literature (Freiberger_2012). In-vitro functional studies indicated that the variant impaired downstream signaling (example-Fried_2011). In addition, a murine model equivalent to the A181E mutation was assessed as having impaired TACI signaling and function in-vivo (Lee_2009). Six ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments of pathogenic/likely pathogenic (n=4, ) uncertain significance (n=1), likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Dec 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001712900.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4, PP1
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Immunoglobulin A deficiency 2
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495993.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Comment:
TNFRSF13B NM_012452.2 exon 4 p.Ala181Glu (c.542C>A): This variant has been reported in the literature in several individuals with features of immunodeficiency and segregating with disease … (more)
TNFRSF13B NM_012452.2 exon 4 p.Ala181Glu (c.542C>A): This variant has been reported in the literature in several individuals with features of immunodeficiency and segregating with disease in families, most often Common variable immune deficiency (CVID) (selected publications:Salzer 2005 PMID:16007087, Pan Hammerstrom 2007 PMID:17392797, Lee 2009 PMID:19605846, Dong 2010 PMID:20156508, Freiberger2012 PMID:22884984, Janzi 2012 PMID:21850030, Marinez-Gallo 2013 PMID:23237420 Romberg 2013 PMID:24051380) and this variant is listed as one of the most common variants identified in patients with CVID. This variant is present in 2.4% (603/24990) of Finnish alelles including 8 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16940415-G-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:5303). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies (including a murine model) suggest that this variant impacts the protein (Lee 2009 PMID 19605846, Fried 2011 PMID:21419480, Martinez-Gallo 2013 PMID:23237420, Romberg 2013 PMID:24051380) potentially through impaired expression and signaling. Of note, this variant has been identified in family members who do not present with disease and is present at a high frequency, including homozygotes, in assumed unaffected individuals suggesting notable reduced penetrance and/or variable expressivity. In summary, data on this variant is highly suspicious for disease, but the presence of conflicting data requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512731.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PP1 supporting
Geographic origin: Brazil
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Likely pathogenic
(Mar 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523610.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM3, BS2
Clinical Features:
Recurrent infections (present) , Lymphopenia (present) , Lymphadenopathy (present) , Abnormal circulating IgM level (present) , Partial IgA deficiency (present) , Hepatosplenomegaly (present)
Geographic origin: Brazil
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Likely pathogenic
(Dec 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950021.2
First in ClinVar: Oct 02, 2021 Last updated: Dec 24, 2022 |
Comment:
_x000D_ Criteria applied: PS3, PS4
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Uncertain significance
(Sep 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827688.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780566.24
First in ClinVar: Dec 19, 2017 Last updated: May 12, 2024 |
Comment:
TNFRSF13B: PS3, PP1, PS4:Supporting
Number of individuals with the variant: 31
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Pathogenic
(May 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605399.3
First in ClinVar: Sep 30, 2017 Last updated: Feb 09, 2020 |
Comment:
The TNFRSF13B c.542C>A; p.Ala181Glu variant (rs72553883) is reported in the literature in multiple individuals diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013). … (more)
The TNFRSF13B c.542C>A; p.Ala181Glu variant (rs72553883) is reported in the literature in multiple individuals diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013). This variant is also observed in clinically asymptomatic relatives and is found in the Finnish European population with an overall allele frequency of 2.4% (603/24990 alleles, including eight homozygotes) in the Genome Aggregation Database, suggesting it may act as a susceptibility or disease-associated variant, possibly with other genetic and/or environmental factors (Dong 2010). Still, case-control studies demonstrate the p.Ala181Glu variant is significantly enriched in affected individuals (OR >5, p< 0.05) (Pan-Hammarstrom 2007, Dong 2010, Freiberger 2012). Functional characterization of the p.Ala181Glu protein in mice (A144E) and human B-cells indicate disrupted NF-KB signaling and significantly impaired B-cell function (Lee 2009, Fried 2011). Based on available information, the variant is considered to be pathogenic. References: Castigli E et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. Dong X et al. (2010) Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B-A181E mutations in common variable immunodeficiency. Hum Immunol. 71(5):505-11. Freiberger T et al. Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. Hum Immunol. 2012 Nov;73(11):1147-54. Fried A et al. Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jul;128(1):226-228.e1. Martinez-Gallo M et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 Feb;131(2):468-76. Lee J et al. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood. 2009 Sep 10;114(11):2254-62. Pan-Hammarstrom Q et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 Apr;39(4):429-30. Salzer U et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8. (less)
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Pathogenic
(Jan 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Immunoglobulin A deficiency 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366259.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4.
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Pathogenic
(Feb 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Immunoglobulin A deficiency 2
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001530695.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502913.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519878.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
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Pathogenic
(Aug 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321966.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Commonly occurring variant associated with CVID, observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced … (more)
Commonly occurring variant associated with CVID, observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013); Published functional studies demonstrates the A181E variant introduces a negative charge in the transmembrane domain, which disrupts signaling and impairs B-cell function (Lee et al., 2009); 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: 21850030, 26096648, 19629655, 19779048, 22884984, 27609654, 27123465, 30659808, 31530980, 30843876, 21419480, 19605846, 21547394, 19392801, 22076597, 16007087, 18981294, 23237420, 24051380, 26100089, 17392797, 20156508, 27577878, 16007086, 32581362, 34426522, 30739909, 33046446, 33726816) (less)
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Likely pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004026700.2
First in ClinVar: Aug 19, 2023 Last updated: Feb 14, 2024 |
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Likely pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Immunodeficiency, common variable, 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000649857.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 181 of the TNFRSF13B protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 181 of the TNFRSF13B protein (p.Ala181Glu). This variant is present in population databases (rs72553883, gnomAD 2.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (PMID: 16007086, 16007087, 20156508). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5303). 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 TNFRSF13B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 19605846, 21419480, 23237420, 24051380). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Sep 10, 2009)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY, COMMON VARIABLE, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025807.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 sibs with common variable immunodeficiency-2 (240500), Castigli et al. (2005) identified a heterozygous 542C-A transversion in exon 4 of the TNFRSF13B gene that … (more)
In 2 sibs with common variable immunodeficiency-2 (240500), Castigli et al. (2005) identified a heterozygous 542C-A transversion in exon 4 of the TNFRSF13B gene that resulted in an ala181-to-glu (A181E) substitution in the transmembrane domain of TACI. One sib developed B-cell non-Hodgkin lymphoma, and her sister, who also had CVID, had died of gastrointestinal carcinoma. Cellular studies showed that the mutant protein was expressed on B cells. Salzer et al. (2005) identified a heterozygous A181E mutation in a family in which the proband had CVID2 and died of tonsillar carcinoma of epithelial origin. Two other family members who were heterozygous for the mutation had selective IgA deficiency-2 (609529). However, 1 additional mutation carrier was apparently unaffected. This mutation was also identified in 6 individuals with sporadic CVID; 1 individual was homozygous for the mutation. They referred to the nucleotide substitution as 555C-A. Lee et al. (2009) found that the mouse Taci with an A144E mutation, the equivalent of the human A181E mutation, exhibited surface expression and ligand binding, but poor Nfkb (164011) signaling, in transfected cells. Mice expressing A144E on a Taci -/- background had low serum IgA levels and impaired antibody responses to a T-independent antigen. B cells from these mice had reduced capacity to proliferate and secrete IgG1 and IgA in response to Taci ligation. Lee et al. (2009) suggested that the A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions. (less)
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Pathogenic
(Sep 10, 2009)
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no assertion criteria provided
Method: literature only
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IMMUNOGLOBULIN A DEFICIENCY 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025808.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 sibs with common variable immunodeficiency-2 (240500), Castigli et al. (2005) identified a heterozygous 542C-A transversion in exon 4 of the TNFRSF13B gene that … (more)
In 2 sibs with common variable immunodeficiency-2 (240500), Castigli et al. (2005) identified a heterozygous 542C-A transversion in exon 4 of the TNFRSF13B gene that resulted in an ala181-to-glu (A181E) substitution in the transmembrane domain of TACI. One sib developed B-cell non-Hodgkin lymphoma, and her sister, who also had CVID, had died of gastrointestinal carcinoma. Cellular studies showed that the mutant protein was expressed on B cells. Salzer et al. (2005) identified a heterozygous A181E mutation in a family in which the proband had CVID2 and died of tonsillar carcinoma of epithelial origin. Two other family members who were heterozygous for the mutation had selective IgA deficiency-2 (609529). However, 1 additional mutation carrier was apparently unaffected. This mutation was also identified in 6 individuals with sporadic CVID; 1 individual was homozygous for the mutation. They referred to the nucleotide substitution as 555C-A. Lee et al. (2009) found that the mouse Taci with an A144E mutation, the equivalent of the human A181E mutation, exhibited surface expression and ligand binding, but poor Nfkb (164011) signaling, in transfected cells. Mice expressing A144E on a Taci -/- background had low serum IgA levels and impaired antibody responses to a T-independent antigen. B cells from these mice had reduced capacity to proliferate and secrete IgG1 and IgA in response to Taci ligation. Lee et al. (2009) suggested that the A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980282.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Established risk allele
(-)
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no assertion criteria provided
Method: research
|
Common variable immunodeficiency 2
Affected status: unknown
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV002764633.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
The TNFRSF13B c.542C>A (p.Ala181Glu) variant (dbSNP: rs72553883) was identified in ClinVar and was classified as pathogenic x9 (ARUP Laboratories, Centre for Mendelian Genomics University Medical … (more)
The TNFRSF13B c.542C>A (p.Ala181Glu) variant (dbSNP: rs72553883) was identified in ClinVar and was classified as pathogenic x9 (ARUP Laboratories, Centre for Mendelian Genomics University Medical Centre Ljubljana, Baylor, Mayo Clinic, AiLife Diagnostics, Mendelics, GeneDx, OMIM) and likely pathogenic x13 (Genetics Services Laboratory Univerisyt of Chicago, Invitae, LabCorp, Institute of Human Genetics University of Leipzig Medical Center, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, Laboratorio de Genetica e Diagnostico Molecular Hospital Israelita Albert Einstein, CeGaT Center for Human Genetics Tuebingen, Genome Diagnostics Laboratory University Medical Center Utrecht, Genome Diagnostics Laboratory Amsterdam University Medical Center, Diagnostic Laboratory, Department of Genetics University Medical Center Groningen, Joint Genome Diagnostic Labs from Nijmegen and Maastricht Radboudumc and MUMC+, Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC Erasmus Medical Center) in association with common variable immunodeficiency 2/not provided and likely benign by Illumina in association with dominant common variable immune deficiency (Please refer to ClinVar Accession: VCV000005303.37; Variation ID: 5303 for additional information). The variant was observed in the heterozygous, homozygous, and compound heterozygous state, and seen in unaffected individuals indicating variable expressivity and reduced penetrance (Lee et al., 2009; Martinez-Gallo et al., 2013) (verbatim: GeneDx, Accession: SCV000321966.7). In a case-control study of 844 individuals with common variable immune deficiency (CVID) and 3924 controls, this variant was found to be a risk factor for development of CVID (OR 5.60, CI 2.99-10.51) (PMID: 17392797). A meta-analysis of 1,439 CVID patients and 3,558 controls showed that this variant is significantly enriched in CVID patients (PMID: 22884984) (verbatim: Invitae, Accession: SCV000649857.5). The variant was identified in control databases in 1540 of 282092 chromosomes (10 homozygous) at a frequency of 0.005459, and was observed at the highest frequency in the European (Finnish) population in 603 of 24990 chromosomes (freq: 0.02413) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.A181 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic- risk factor for common variable immunodeficiency. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978408.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977739.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978482.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979696.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Common variable immunodeficiency 2
Affected status: unknown
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV000840265.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Prenatal maternal abnormality (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the neck (present) , Abnormality … (more)
Premature birth (present) , Prenatal maternal abnormality (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the neck (present) , Abnormality of eye movement (present) , Hip dysplasia (present) , Abnormality of cardiovascular system morphology (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-12-04
Testing laboratory interpretation: Likely pathogenic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia. | Sogkas G | Annals of the rheumatic diseases | 2021 | PMID: 33046446 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature. | Torti E | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30739909 |
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. | Romberg N | The Journal of allergy and clinical immunology | 2015 | PMID: 26100089 |
CVID-associated TACI mutations affect autoreactive B cell selection and activation. | Romberg N | The Journal of clinical investigation | 2013 | PMID: 24051380 |
TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. | Martinez-Gallo M | The Journal of allergy and clinical immunology | 2013 | PMID: 23237420 |
Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. | Freiberger T | Human immunology | 2012 | PMID: 22884984 |
Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children. | Janzi M | Genes and immunity | 2012 | PMID: 21850030 |
Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. | Fried AJ | The Journal of allergy and clinical immunology | 2011 | PMID: 21419480 |
Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B-A181E mutations in common variable immunodeficiency. | Dong X | Human immunology | 2010 | PMID: 20156508 |
Role of TNFRSF13B variants in patients with common variable immunodeficiency. | Martínez-Pomar N | Blood | 2009 | PMID: 19779048 |
The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. | Lee JJ | Blood | 2009 | PMID: 19605846 |
Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. | Pan-Hammarström Q | Nature genetics | 2007 | PMID: 17392797 |
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. | Salzer U | Nature genetics | 2005 | PMID: 16007087 |
TACI is mutant in common variable immunodeficiency and IgA deficiency. | Castigli E | Nature genetics | 2005 | PMID: 16007086 |
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Text-mined citations for rs72553883 ...
HelpRecord last updated May 27, 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.