ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.260T>A (p.Ile87Asn) (rs72553877)

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Total submissions: 4
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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
Invitae RCV000800201 SCV000939901 likely pathogenic Common variable immunodeficiency 2 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 87 of the TNFRSF13B protein (p.Ile87Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs72553877, ExAC 0.07%). This variant has been observed in combination with another TNFRSF13B variant in individuals affected with common variable immunodeficiency (CVID) (PMID: 22627058, 27123465). In addition, it has been observed in heterozygous individuals affected with CVID (PMID: 22884984, 22697072, 27123465, 30290665, 31681265). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 618436). Experimental studies have shown that this missense change leads to impaired receptor binding and NF-kB activity (PMID: 21419480, 21458042). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000800201 SCV001525429 uncertain significance Common variable immunodeficiency 2 2020-07-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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