ClinVar Miner

Submissions for variant NM_003998.4(NFKB1):c.1870G>A (p.Ala624Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV003338042 SCV004046911 uncertain significance Immunodeficiency, common variable, 12 criteria provided, single submitter clinical testing The c.1870G>A (p.Ala624Thr) missense variant in NFKB1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala624Thr variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 624 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ala624Thr in NFKB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
Labcorp Genetics (formerly Invitae), Labcorp RCV003777441 SCV004647658 uncertain significance not provided 2022-12-03 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 NFKB1 protein function. This variant has not been reported in the literature in individuals affected with NFKB1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 624 of the NFKB1 protein (p.Ala624Thr).

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