Submissions for variant NM_012452.3(TNFRSF13B):c.605G>A (p.Arg202His)

gnomAD frequency: 0.00076  dbSNP: rs104894649

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000397011	SCV000400913	likely benign	Common Variable Immune Deficiency, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005627	SCV000649860	benign	Immunodeficiency, common variable, 2	2024-01-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730698	SCV000858457	uncertain significance	not provided	2017-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000730698	SCV000892512	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532954	SCV001748770	likely benign	not specified	2021-06-25	criteria provided, single submitter	clinical testing	Variant summary: TNFRSF13B c.605G>A (p.Arg202His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 249890 control chromosomes. The observed variant frequency is approximately 278.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), strongly suggesting that the variant is benign. c.605G>A has been reported in the literature in individuals affected with Common Variable Immunodeficiency and IgA deficiency, however without strong supporting evidence of pathogenicity and often also being found in controls (Castigli_2005, Salzar_2005, Castigli_2007, Lopez-Mejias_2009, Freiberger_2012, DeVries_2011, Karaca_2018, Pulvirenti_2016). The variant has been reported to not segregate with disease in 3 families, including the variant being found in unaffected family members and affected family members lacking the variant (Pan-Hammarstrom_2007, Speletas_2011). Experimental evidence showed the variant had little or no inhibitory effect on signaling via NF-kB and AP-1 and did not impair the interaction with MyD88, TRAF2, TRAF5, TRAF6 or CAML (He_2010). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two labs classified the variant as benign/likely benign while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000730698	SCV001781025	uncertain significance	not provided	2023-06-11	criteria provided, single submitter	clinical testing	Identified as a single heterozygous variant in patients with common variable immune deficiency (CVID) in the published literature; however also found at a similar frequency in controls, suggesting R202H may not contribute to risk of CVID (Salzer et al., 2005; Castigli et al., 2005; Pan-Hammarstrm et al., 2007; Freiberger et al., 2012); Published functional studies demonstrate no damaging effect, as R202H retained NF-kB activation and ligand binding (Bacchelli et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16007087, 16007086, 23956760, 21850030, 22884984, 19392801, 34426522, 21458042, 17392797, 30090215, 30269248, 33206719, 35655776)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000730698	SCV002049998	uncertain significance	not provided	2021-09-03	criteria provided, single submitter	clinical testing	The TNFRSF13B c.605G>A; p.Arg202His variant (rs104894649) is reported in literature in six individuals affected with common variable immune deficiency (Janzi 2012, Pan-Hammarström 2007, Salzer 2005) and two individuals with IgAD (Pan-Hammarström 2007). This variant was more frequently observed in control individuals compared to CVID cohort, though an enrichment was observed in IgAD cohort compared to controls with an odds ratio of 5.91 (1.94~18.07, 95% CI) (Pan-Hammarström 2007). Data obtained from a single IgAD patient suggested that this variant does not alter IgA levels (Janzi 2012). Functional analyses of the variant protein by luciferase reporter assay showed no impact on downstream signaling pathway components (He 2010). This variant is also reported in ClinVar (Variation ID: 5304). This variant is found in the non-Finnish European population with an allele frequency of 0.12% (156/127656 alleles) in the Genome Aggregation Database. The arginine at codon 202 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.554). Due to conflicting information, the clinical significance of this variant is uncertain at this time.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001532954	SCV004847972	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	The p.Arg202His variant in TNFRSF13B has been reported in multiple individuals with combined immunodeficiency or IgA deficiency, however it has also been found at similar frequencies in control populations and was not found to segregate with individuals in a family (Pan-Hammarstrom 2007 PMID: 17392797, Lopez-Mejias 2009 PMID: 19392801, Janzi 2012 PMID: 21850030, Speletas 2013 PMID: 23956760, van Schouwenburg 2015 PMID: 26122175). This variant has been identified in 0.14% (5/3468) of Ashkenazi Jewish and 0.1% (81/68030) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v 3.1.2). This variant has also been reported in ClinVar (Variation ID 5304). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant does not impact protein function (Bacchelli 2011 PMID: 21458042, He 2010 PMID: 20676093); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign/its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS3_Moderate, BS4_Supporting.
OMIM	RCV000005627	SCV000025809	pathogenic	Immunodeficiency, common variable, 2	2005-08-01	no assertion criteria provided	literature only