ClinVar Miner

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

gnomAD frequency: 0.00158  dbSNP: rs148695964
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Total submissions: 6
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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
PreventionGenetics, part of Exact Sciences RCV003905029 SCV004718961 likely benign IKBKG-related disorder 2023-09-17 criteria provided, single submitter 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).
UniProtKB/Swiss-Prot RCV000059069 SCV000090590 not provided not provided no assertion provided not provided
OMIM RCV001172482 SCV001335512 pathogenic Immunodeficiency 33 2023-12-14 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

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