Submissions for variant NM_012452.3(TNFRSF13B):c.215G>A (p.Arg72His)

gnomAD frequency: 0.00261  dbSNP: rs55916807

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000266832	SCV000400919	likely benign	Common Variable Immune Deficiency, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000762233	SCV000521294	likely benign	not provided	2018-03-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18981294, 17392797, 16007087, 17983875, 17464555, 22884984, 26122175, 17392798, 32581362)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086588	SCV000769961	likely benign	Immunodeficiency, common variable, 2	2025-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762233	SCV000892515	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TNFRSF13B: PM5, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000762233	SCV001160284	likely benign	not provided	2020-03-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000441515	SCV001432045	likely benign	not specified	2020-08-04	criteria provided, single submitter	clinical testing	Variant summary: TNFRSF13B c.215G>A (p.Arg72His) results in a non-conservative amino acid change located in the TACI, cysteine-rich domain (IPR015384) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 394334 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 exomes dataset, and v3 genomes dataset), including 2 homozygotes. The observed variant frequency is considerably higher than the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype, strongly suggesting that the variant is benign. The variant, c.215G>A, also has been reported in the literature (in heterozygous and compound heterozygous state) in individuals affected with Common Variable Immunodeficiency, but has also been observed in unaffected individuals and family members (e.g. Salzer_2005, Freiberger_2012, Pulvirenti_2016). These reports do not provide unequivocal conclusions about association of the variant with Common Variable Immunodeficiency. The variant was found at frequencies comparable in CVID patient cohorts and healthy controls in multiple case-control studies (e.g. Salzer_2009, van Schouwenburg_2015) and in a meta-analysis of cases and controls from the literature (Freiberger_2012). A publication reported experimental evidence and demonstrated decreased production of IgG and IgA after APRIL stimulation of B cells derived from a patient carrying the variant in heterozygous state. However, in this study B cells of subjects with CVID but no TNFRSF13B mutations were at least as dysfunctional as B cells of subjects with CVID, who had monoallelic- or biallelic TNFRSF13B mutations; therefore, this study doesn't allow convincing conclusions about the variant effect (Zhang_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224261	SCV003920577	likely benign	Immunodeficiency, common variable, 2; Immunoglobulin A deficiency 2	2022-07-15	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in several individuals with common variable immunodeficiency (CVID) as well as in at least 2 individuals with antibody deficiency (Salzer 2005 PMID:16007087, Pan-Hammarstrom 2007 PMID:17392797, Zhang 2007 PMID:179838875, Freiberger 2012 PMID:22884984, Turro 2020 PMID:32581362, Rojas-Restrepo 2021 PMID:34975878). Of note, multiple publications list this variant as a polymorphism. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.4% (314/68020) including 2 homozygotes (https://gnomad.broadinstitute.org/variant/17-16948968-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:322027). This variant amino acid Histidine (His) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000762233	SCV005212255	likely benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762233	SCV001739658	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000762233	SCV001799106	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762233	SCV001968370	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000762233	SCV001977875	likely benign	not provided		no assertion criteria provided	clinical testing