Submissions for variant NM_001556.3(IKBKB):c.1173C>A (p.Asp391Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003091746	SCV003480842	uncertain significance	Severe combined immunodeficiency due to IKK2 deficiency	2022-10-10	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt IKBKB protein function. This variant has not been reported in the literature in individuals affected with IKBKB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 391 of the IKBKB protein (p.Asp391Glu).
Neuberg Centre For Genomic Medicine, NCGM	RCV003340629	SCV004047586	uncertain significance	Immunodeficiency 15a		criteria provided, single submitter	clinical testing	The c.1173C>A (p.Asp391Glu) missense variant in IKBKB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp391Glu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Asp at position 391 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).