Submissions for variant NM_012452.3(TNFRSF13B):c.236A>G (p.Tyr79Cys)

gnomAD frequency: 0.00021  dbSNP: rs72553876

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723608	SCV000331382	uncertain significance	not provided	2015-11-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000327211	SCV000605398	likely pathogenic	not specified	2017-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648139	SCV000769953	uncertain significance	Immunodeficiency, common variable, 2	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the TNFRSF13B protein (p.Tyr79Cys). This variant is present in population databases (rs72553876, gnomAD 0.05%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID), IgG subclass deficiency, and/or primary immune disorders (PMID: 18981294, 22884984, 32581362, 34093558). ClinVar contains an entry for this variant (Variation ID: 281110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNFRSF13B protein function. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 18954329, 21419480, 21458042). 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.
GeneDx	RCV000723608	SCV001789899	likely pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Identified in the presence of a second TNFRSF13B variant in siblings with IgG subclass deficiency, one of whom had recurrent infections requiring IVIG therapy; however, their heterozygous mother was unaffected and father with dysgammaglobulinemia or IgG subclass deficiency was not tested (PMID: 18981294); Identified the heterozygous state in patients with features of TNFRSF13B-related immunodeficiency, though segregation information was not provided (PMID: 31980526, 34093558); Surface expression studies support that the Y79C variant is damaging to the TNFRSF13B protein (PMID: 21419480); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18954329, 21458042, 22884984, 32581362, 21419480, Pundit2023[abstract], 18981294, 34093558, 31980526)
Revvity Omics, Revvity	RCV000723608	SCV002020243	likely pathogenic	not provided	2022-06-26	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000648139	SCV002512526	uncertain significance	Immunodeficiency, common variable, 2	2021-04-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 supporting, PP3
Mendelics	RCV000327211	SCV002516100	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947825	SCV004759997	likely pathogenic	TNFRSF13B-related disorder	2023-12-02	no assertion criteria provided	clinical testing	The TNFRSF13B c.236A>G variant is predicted to result in the amino acid substitution p.Tyr79Cys. This variant has been reported in the compound heterozygous state in two individuals with IgG subclass deficiency from the same family (Salzer et al. 2009. PubMed ID: 18981294). Of note, this variant was also seen in the heterozygous state in a healthy member of that same family (Salzer et al. 2009. PubMed ID: 18981294). Functional analysis showed that the c.236A>G variant leads to a reduction in protein activity as compared to wild-type (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.