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

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 25, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002054418.9

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]

Condition(s)

Name:
Immunodeficiency, common variable, 2
Synonyms:
ANTIBODY DEFICIENCY DUE TO TACI DEFECT; HYPOGAMMAGLOBULINEMIA DUE TO TACI DEFICIENCY; Hypogamma-globulinemia, acquired; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009413; MedGen: C3150354; Orphanet: 1572; OMIM: 240500
Name:
Immunoglobulin A deficiency 2 (IGAD2)
Synonyms:
Immunoglobulin A, selective deficiency of, TACI related; IgA, selective deficiency of, TACI related
Identifiers:
MONDO: MONDO:0012291; MedGen: C1836032; OMIM: 609529

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002495994Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 25, 2020) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV002495994.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

TNFRSF13B:NM_012452.2:c.310T>C:p.Cys104Arg: This variant has been reported in the literature in numerous individuals with Combined Variable Immune Deficiency (CVID) in the heterozygous, homozygous and compound heterozygous state and is listed as the most common variant reported in association with this condition (Selected Publications: Salzer 2005 PMID:16007087, Berglund 2006 PMID:16630947, Pan-Hammarstrom 2007 PMID:17392797, Barroeta-Seijas 2012 PMID:22697072, Koopmans 2013 PMID:22983507, Martinez-Galllo 2013 PMID:23237420, Rudilla 2019 PMID:31681265). This variant has been identified to segregate with disease in multiple different family members, also in the heterozygous, compound heterozygous and homozygous state. However, this variant has been identified in multiple individuals who do not present with disease (including in the homozygous state) even within the same family, suggesting that this variant has significant reduced penetrance (Koopmans 2013 PMID:22983507, Martinez-Galllo 2013 PMID:23237420). This variant is present in 0.7% (109/15278) of Latino alleles, including 1 homozygote and is present at similar frequencies across different ethnicities in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16948873-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance (Uncertain significance) to Pathogenic (Variation ID:5302). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Numerous functional studies including mouse models have demonstrated the impact of this variant by reducing expression on the surface of B-cells, impairing bindings with BAFF and APRIL and defective antibody production (Salzer 2005 PMID:16007087, Lee 2010 PMID:20889194, Fried 2011 PMID:21419480, Martinez-Galllo 2013 PMID:23237420). In summary, this variant is classified as likely pathogenic based on extensive studies, but may be best considered in the context of a non-mendelian risk allele.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024