ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.605G>A (p.Arg202His) (rs104894649)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000397011 SCV000400913 likely benign Common Variable Immune Deficiency, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000005627 SCV000649860 benign Common variable immunodeficiency 2 2020-11-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000730698 SCV000858457 uncertain significance not provided 2017-11-30 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik 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 2019-08-29 criteria provided, single submitter clinical testing 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; 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); This variant is associated with the following publications: (PMID: 33206719, 30269248, 30090215, 21458042, 19392801, 16007086, 16007087, 17392797, 22884984, 21850030, 23956760)
OMIM RCV000005627 SCV000025809 pathogenic Common variable immunodeficiency 2 2005-08-01 no assertion criteria provided literature only

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