NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (15 submissions)
Last evaluated:: Jul 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000403933.62

Allele description [Variation Report for NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg)]

NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg)

Gene:

TNFRSF13B:TNF receptor superfamily member 13B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg)

HGVS:

NC_000017.11:g.16948873A>G
NG_007281.1:g.28216T>C
NM_012452.3:c.310T>CMANE SELECT
NP_036584.1:p.Cys104Arg
NP_036584.1:p.Cys104Arg
LRG_120t1:c.310T>C
LRG_120:g.28216T>C
LRG_120p1:p.Cys104Arg
NC_000017.10:g.16852187A>G
NM_012452.2:c.310T>C
NM_012452.3:c.310T>C
O14836:p.Cys104Arg
p.(Cys104Arg)

Protein change:

C104R; CYS104ARG

Links:

UniProtKB: O14836#VAR_024027; OMIM: 604907.0001; dbSNP: rs34557412

NCBI 1000 Genomes Browser:

rs34557412

Molecular consequence:

NM_012452.3:c.310T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329550	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 10, 2022)	germline	clinical testing	Citation Link,
SCV000605391	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Sep 27, 2023)	germline	clinical testing	Citation Link,
SCV000610665	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000927312	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Uncertain significance (Jun 26, 2017)	germline	clinical testing	Citation Link,
SCV001250126	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV001712902	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 29, 2020)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 16007087, 16630947, 17392797, 17392798, 18981294, 19779048, 20889194, 21419480, 22697072, 22983507, 26727773, 26100089, 27123465, 29114388, 29867916, 30665703, 25741868
SCV001742791	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001931341	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001954885	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001969656	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001977672	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002020242	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002070496	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 20, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503376	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 9, 2022)	germline	clinical testing	PubMed (28) [See all records that cite these PMIDs] 16007087, 29921932, 29114388, 22697072, 16630947, 29146883, 29867916, 22884984, 21419480, 21850030, 22983507, 20889194, 26727773, 23237420, 25174870, 17392797, 29555771, 27123465, 33258288, 26100089, 24051380, 31681265, 27577878, 32499645, 32581362, 30665703, 31618753, 25741868
SCV004242767	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	40	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency.

Castigli E, Wilson S, Garibyan L, Rachid R, Bonilla F, Schneider L, Morra M, Curran J, Geha R.

Nat Genet. 2007 Apr;39(4):430-1. No abstract available.

PubMed [citation]

PMID:: 17392798

Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.

Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, Bergbreiter A, Hagena T, Birmelin J, Plebani A, Webster AD, Peter HH, Suez D, Chapel H, McLean-Tooke A, Spickett GP, Anover-Sombke S, Ochs HD, Urschel S, Belohradsky BH, Ugrinovic S, Kumararatne DS, et al.

Blood. 2009 Feb 26;113(9):1967-76. doi: 10.1182/blood-2008-02-141937. Epub 2008 Nov 3.

PubMed [citation]

PMID:: 18981294
PMCID:: PMC2651012

See all PubMed Citations (31)

Details of each submission

From GeneDx, SCV000329550.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported previously in association with both autosomal dominant and autosomal recessive forms of CVID and immunoglobulin A deficiency; however, this variant is most commonly associated with autosomal recessive inheritance (Salzer et al., 2009; Barroeta Seijas et al., 2012; Speletas et al., 2013; Martinez-Gallo et al., 2013; Lucena et al., 2015); Published functional studies demonstrate C104R results in reduced surface expression and elimination of ligand binding, supporting a damaging effect (Lee et al., 2010; Fried et al., 2011); 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: 25326637, 24051380, 17392797, 30269248, 17492055, 26727773, 22983507, 22697072, 20889194, 23956760, 23237420, 16007086, 19210517, 16007087, 18981294, 22884984, 25174870, 21850030, 27123465, 26100089, 27577878, 16630947, 29146883, 29867916, 29555771, 29921932, 29114388, 30665703, 31681265, 31618753, 32499645, 32581362, 21419480, 34573280, 34426522, 34210994, 30755392, 33425813, 33258288, 32441320, 32531373, 33726816)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605391.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The TNFRSF13B c.310T>C; p.Cys104Arg variant (rs34557412) has been reported in patients diagnosed with common variable immunodeficiency, and the association with the disease was found to be statistically significant (odds ratio 4.16 (1.98-8.74); Pan-Hammarstrom 2007). Additionally, functional studies show that this variant disrupts protein signaling (Martinez-Gallo 2013, Salzer 2005). However, this variant does not always segregate with disease in families (Poodt 2009, Koopmans 2013) and the variant is often observed in clinically asymptomatic first-degree relatives and healthy controls (Barroeta Seijas 2012, Martinez-Pomar 2009). This variant is reported in ClinVar (Variation ID: 5302), and is found in the general population with an overall allele frequency of 0.35% (983/282890 alleles, including 4 homozygotes) in the Genome Aggregation Database. Based on available information, this variant is considered to be a pathogenic CVID-associated variant with variable penetrance, that may act in co-existence with other genetic and/or environmental factors (Koopmans 2013). Barroeta Seijas AB et al. The impact of TACI mutations: from hypogammaglobulinemia in infancy to autoimmunity in adulthood. Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):407-14. PMID: 22697072. Koopmans et al. Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). J Clin Immunol. 2013 33(1):68-73. PMID: 22983507. Martínez-Pomar N et al. Role of TNFRSF13B variants in patients with common variable immunodeficiency. Blood. 2009 Sep 24;114(13):2846-8. PMID: 19779048. Martinez-Gallo et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 131(2):468-476. PMID: 23237420. Pan-Hammarstrom et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 39(4):429-30. PMID: 17392797. Poodt AE et al. TACI mutations and disease susceptibility in patients with common variable immunodeficiency. Clin Exp Immunol. 2009 Apr;156(1):35-9. PMID: 19210517. 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. PMID: 16007087.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610665.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.00582	not provided	not provided

From Blueprint Genetics, SCV000927312.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001250126.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	38	not provided	not provided	clinical testing	not provided

Description

TNFRSF13B: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		38	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001712902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (17)

Description

PS3, PS4_moderate, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742791.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931341.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954885.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001969656.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001977672.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020242.3

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002070496.1

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

Description

DNA sequence analysis of the TNFRSF13B gene demonstrated a sequence change, c.310T>C, in exon 3 that results in an amino acid change, p.Cys104Arg. This sequence change has been described in the gnomAD database with a relatively high population frequency of 0.54% in European populations (dbSNP rs34557412). The p.Cys104Arg change affects a highly conserved amino acid residue located in a domain of the TNFRSF13B protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys104Arg substitution. The p.Cys104Arg change has been reported in the homozygous, compound heterozygous, and heterozygous states in many individuals affected with common variable immunodeficiency (CVID) (PMID: 16007087, 17392797, 22697072, 27123465, 24051380, 19779048). Individuals who are heterozygous for this sequence change have been reported with an increased number of autoreactive B-cells in the bone marrow (PMID: 24051380). This sequence has also been seen in the heterozygous state in multiple unaffected individuals, however functional studies on B cells of these individuals show impaired function compared to unaffected individuals without variants in TNFRSF13B (PMID: 23237420, 24051380). The p.Cys104Arg change has been reported to segregate with disease in several families; however, it appears to have reduced penetrance (PMID: 16007087, 19779048, 22983507, 22697072, 22884984, 23237420). Functional studies have demonstrated that this sequence change affects ligand binding and reduces protein expression (PMID: 16007087, 21419480, 23237420). This sequence change is predicted to confer an increased risk for the development of CVID and is may confer an increased risk for lymphoma. We interpret this change as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002503376.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (28)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004242767.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

Relating variation to medicine