ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.311G>A (p.Cys104Tyr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000799248 SCV000938902 likely pathogenic Common variable immunodeficiency 2 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 104 of the TNFRSF13B protein (p.Cys104Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs72553879, ExAC 0.03%). This variant has been observed to segregate with common variable immunodeficiency (CVID) in a family (PMID: 18981294). In addition, it has been reported in unrelated individuals affected with CVID and IgA deficiency (PMID: 27123465, 22884984). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Cys104 amino acid residue in TNFRSF13B have been observed in affected individuals (PMID: 16007087, 19779048, 22983507, 22697072, 22884984, 23237420). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

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