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

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	2019-09-18	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). This variant has been reported to affect TNFRSF13B protein function (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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000658772	SCV000780567	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing