Submissions for variant NM_012452.3(TNFRSF13B):c.260T>A (p.Ile87Asn)

gnomAD frequency: 0.00034  dbSNP: rs72553877

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756794	SCV000884707	likely pathogenic	not provided	2017-10-31	criteria provided, single submitter	clinical testing	The p.Ile87Asn variant (rs72553877) has been reported in the heterozygous and compound heterozygous state in multiple families and individuals diagnosed with common variable immunodeficiency (CVID), asthma, or lymphoproliferative disorders (Freiberger 2012, Janzi 2012, Lougaris 2012, Salzer 2009, and Speletas 2013). This variant has also been observed by our laboratory in a patient who inherited the variant from his unaffected father and was reported to have chronic infections and IgA deficiency. Functional evidence demonstrates that the p.Ile87Asn variant causes a defect in ligand binding as well as reduced activation of NFkB signaling (Fried 2011, Lougaris 2012, and Salzer 2009). The p.Ile87Asn variant is also listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.068% in the non-Finnish European population (identified in 86 out of 126,692 chromosomes), but was not detected in the homozygous state. The isoleucine at codon 87 is moderately conserved considering 10 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the TNFRSF13B protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Therefore, based on the available evidence, the p.Ile87Asn variant is classified as likely pathogenic.
Blueprint Genetics	RCV000756794	SCV000928281	uncertain significance	not provided	2019-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800201	SCV000939901	pathogenic	Immunodeficiency, common variable, 2	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 87 of the TNFRSF13B protein (p.Ile87Asn). This variant is present in population databases (rs72553877, gnomAD 0.07%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 22627058, 22697072, 22884984, 27123465, 30290665, 31681265). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 618436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNFRSF13B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 21419480, 21458042). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000800201	SCV001525429	likely pathogenic	Immunodeficiency, common variable, 2		criteria provided, single submitter	clinical testing
GeneDx	RCV000756794	SCV001792998	pathogenic	not provided	2024-08-14	criteria provided, single submitter	clinical testing	Reported as a single heterozygous variant in patients with common variable immune deficiency or selective IgA deficiency in the published literature, as well as in unaffected individuals (PMID: 22697072, 22930256, 27123465); Published functional studies demonstrate no effect on cell surface expression, but a significant reduction in signaling (PMID: 21419480); 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: 21041728, 34975878, 23956760, 17697196, 18981294, 21850030, 22884984, 22627058, 19494827, 21458042, 19629655, 28554560, 22930256, 27123465, 30269248, 30290665, 31681265, 34426522, 31589614, 35686370, 34573280, 32581362, 34441032, 37678716, 37652172, 22697072, 21419480)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844233	SCV002103854	likely pathogenic	Common variable immunodeficiency	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: TNFRSF13B c.260T>A (p.Ile87Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 254886 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (0.00046 vs 0.0024), allowing no conclusion about variant significance. c.260T>A has been reported in heterozygous and presumed compound heterozygous state in individuals affected with Common Variable Immunodeficiency (e.g. Bacchelli_2007, Pan-Hammarstrom_2008, PanSalzer_2009, Lougaris_2012, Rojas-Restrepo_2021, Fioredda_2022, Peng_2023, Salih_2023). In some families the variant has been inherited from an unaffected parent and authors described this allele as a risk allele (Peng_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant resulted in decreased activity (Salzer_2009, Fried_2011, Lougaris_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18978466, 19629655, 17697196, 21419480, 21850030, 22627058, 18200502, 34975878, 18981294, 37678716, 37652172, 35686370). ClinVar contains an entry for this variant (Variation ID: 618436). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000756794	SCV002545886	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	TNFRSF13B: PS4:Moderate, PP1, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000800201	SCV005368208	likely pathogenic	Immunodeficiency, common variable, 2	2024-07-18	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PS3_MOD
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000800201	SCV005398975	uncertain significance	Immunodeficiency, common variable, 2	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 2 (MIM#240500) and immunoglobulin A deficiency 2 (MIM#609529). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with monoallelic or biallelic variants have been reported (PMIDs: 34210994, 34441032). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 34210994). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (771 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TACI, cysteine-rich domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported three times as pathogenic, three times as likely pathogenic and twice as a VUS (ClinVar). It has also been reported in multiple individuals with common variable immunodeficiency in the literature in both the heterozygous and compound heterozygous state, however has also been reported in many unaffected heterozygous individuals (PMIDs: 22884984, 18981294, 22627058, 37678716, 27123465, 34441032, 33838017). (I) 0906 - Segregation evidence for this variant is inconclusive. There are conflicting reports of individuals inheriting this variant from an affected parent (PMID: 18981294) as well as from unaffected parents (PMID: 37678716). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cells expressing this variant demonstrated partially reduced ligand binding and impaired NFAT signalling when compared to wildtype cells (PMIDs: 21419480, 22627058). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000800201	SCV002573410	pathogenic	Immunodeficiency, common variable, 2		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV002508946	SCV002818329	not provided	IgAD1; Immunodeficiency, common variable, 2		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-12-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.