ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.515G>A (p.Cys172Tyr) (rs751216929)

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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 RCV000658772 SCV000780567 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000658772 SCV000617813 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing The C172Y variant in the TNFRSF13B gene has been reported previously in the heterozygous state in an individual with common variable immunodeficiency (CVID), however, it is unknown if this individual was screened for variants in other genes associated with CVID (Zhang et al., 2007). The C172Y variant is observed in 4/10138 (0.04%) alleles from individuals of Ashkenazi Jewish background, including 1 homozygous individual in large population cohorts (Lek et al., 2016). The C172Y 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. This substitution occurs at a position that is not conserved. Functional studies demonstrate that the C172Y variant significantly decreases activation of NF-kB and NFAT transcription factors (Fried et al., 2011). We interpret C172Y as a variant of uncertain significance.
Invitae RCV000648142 SCV000769956 uncertain significance Common variable immunodeficiency 2 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 172 of the TNFRSF13B protein (p.Cys172Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs751216929, ExAC 0.03%), including at least one homozygous individual. This variant has been reported as heterozygous in the literature in several individuals with TNFRSF13B-related disease (PMID: 17983875, 19629655, 27123465). ClinVar contains an entry for this variant (Variation ID: 449548). Experimental studies have shown that this missense change impairs the signaling function of the encoded protein (PMID: 21419480). 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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