Submissions for variant NM_001099857.5(IKBKG):c.169G>A (p.Glu57Lys)

gnomAD frequency: 0.00158  dbSNP: rs148695964

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000059069	SCV000281293	benign	not provided	2015-10-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000059069	SCV001150543	likely benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059069	SCV000090590	not provided	not provided		no assertion provided	not provided
OMIM	RCV001172482	SCV001335512	pathogenic	Immunodeficiency 33	2024-07-18	no assertion criteria provided	literature only
Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP)- HUVH-VHIR, Vall d'Hebron University Hospital	RCV003493432	SCV004023254	uncertain significance	Common variable immunodeficiency		no assertion criteria provided	clinical testing	We found the IKBKG c.169G>A / p.Glu57Lys variant in an adult female patient with common variable immunodeficiency (CVID). The variant has a very low frequency in the reference population databases (gnomad v3.1.2 MAF:0.001). The patient had skewed X chromosome inactivation, causing predominant expression of the mutated allele. Different studies reported functional alterations of the nuclear factor-κB (NF-κB) pathway: Gautheron et al showed that p.Glu57Lys variant is associated with a defect in TRAF6-dependent signaling pathways (i.e. IL-1 beta signaling) (PMID: 20529958). Frans et al showed a decrease of IL6 induction upon stimulation with IL-1 beta and TNF-alpha in SV40-transformed NEMO -/- fibroblasts transduced with p.Glu57Lys NEMO (PMID: 28993958). The IKBKG p.Glu57Lys variant has been reported in female patients with mild forms of incontinentia pigmenti (IP) and in a male patient with immunodeficiency (including hypogammaglobulinemia) but without ectodermal dysplasia (PMIDs: 15229184, 20529958, 28993958). The p.Glu57Lys variant has also been identified in healthy individuals (both males and females), consistent with its relatively high allele frequency. Therefore, we consider it a Variant of Uncertain Significance
PreventionGenetics, part of Exact Sciences	RCV003905029	SCV004718961	likely benign	IKBKG-related disorder	2023-09-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).