ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.577T>C (p.Cys193Arg) (rs764125338)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762231 SCV000892513 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000762231 SCV000617097 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing The C193R variant in the TNFRSF13B gene has been reported previously in an individual with features of both autoimmune lymphoproliferative syndrome and CVID; however, this individual also harbored a variant in the CASP9 gene that may also have contributed to the phenotype (Clemente et al., 2015). Additionally, this individual harbored a nonsense variant on the same TNFRSF13B allele (in cis). The C193R variant is observed in 6/66,548 (0.009%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The C193R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret C193R as a variant of uncertain significance.
Invitae RCV000695310 SCV000823800 uncertain significance Common variable immunodeficiency 2 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 193 of the TNFRSF13B protein (p.Cys193Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs764125338, ExAC 0.009%). This variant has been reported in an individual affected with autoimmune lymphoproliferative syndrome and common variable immunodeficiency (PMID: 25569260). ClinVar contains an entry for this variant (Variation ID: 449227). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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