Submissions for variant NM_012452.3(TNFRSF13B):c.512T>G (p.Leu171Arg)

gnomAD frequency: 0.00012  dbSNP: rs143027621

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506368	SCV000605393	pathogenic	not specified	2017-01-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648134	SCV000769948	uncertain significance	Immunodeficiency, common variable, 2	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 171 of the TNFRSF13B protein (p.Leu171Arg). This variant is present in population databases (rs143027621, gnomAD 0.02%). This variant has been reported as homozygous, compound heterozygous, and heterozygous in individuals and families affected with common variable immunodeficiency (PMID: 17983875, 17392798, 19779048, 22697072, 23237420, 32581362, 31530980). It has also been observed as heterozygous in asymptomatic individuals from these same families (PMID: 23237420, 22697072). ClinVar contains an entry for this variant (Variation ID: 440340). ClinVar contains an entry for this variant (Variation ID: 440340). 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: 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 Center for Human Genetics Tuebingen	RCV000762232	SCV000892514	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000762232	SCV000928296	uncertain significance	not provided	2019-03-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000762232	SCV001712901	likely pathogenic	not provided	2021-03-30	criteria provided, single submitter	clinical testing	PS3, PP3
GeneDx	RCV000762232	SCV001986310	uncertain significance	not provided	2024-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate unstable protein with negligible ligand binding (PMID: 21419480); Reported in an individual with lower respiratory track infections, HSV infections, and giardiasis; however her heterozygous mother was reportedly healthy and the variant did not segregate with autoimmunity, vitiligo, and thyroiditis in the extended family members (PMID: 22697072); 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: 17983875, 37711607, 35570134, 34247095, 32344018, 19779048, 23237420, 17392798, 31530980, 32581362, 21419480, 22697072)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000648134	SCV003807463	likely pathogenic	Immunodeficiency, common variable, 2	2022-09-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 strong, PP3 supporting
PreventionGenetics, part of Exact Sciences	RCV003902813	SCV004727113	uncertain significance	TNFRSF13B-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The TNFRSF13B c.512T>G variant is predicted to result in the amino acid substitution p.Leu171Arg. This variant has been reported in the homozygous, compound heterozygous and heterozygous states in individuals with common variable immunodeficiency (Castigli et al. 2007. PubMed ID: 17392798; Zhang et al. 2007. PubMed ID: 17983875; Martínez-Pomar et al. 2009. PubMed ID: 19779048; Barroeta Seijas et al. 2012. PubMed ID: 22697072; Martinez-Gallo et al. 2013. PubMed ID: 23237420). This variant has also been observed in the heterozygous state in asymptomatic individuals (Family of patient C.I - father C.II and sister C.III, Martinez-Gallo et al. 2013. PubMed ID: 23237420). The variant did not segregate with disease in another family with autoimmunity, vitiligo, and thyroiditis (Family C, Barroeta Seijas et al. 2012. PubMed ID: 22697072). Of note, in that family all members (mother, father, sister, and proband) were reported healthy, but had symptoms of autoimmune diseases; however only the proband was diagnosed with common variable immunodeficiency. Functional studies demonstrated that the p.Leu171Arg variant impacted the expression and function of the TNFRSF13B protein (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations in the ClinVar database, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/440340/). While this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.