Submissions for variant NM_002485.5(NBN):c.1147G>A (p.Glu383Lys)

gnomAD frequency: 0.00001  dbSNP: rs772909239

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528325	SCV000634200	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 383 of the NBN protein (p.Glu383Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs772909239, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 461491). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV000573284	SCV000670226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-19	criteria provided, single submitter	clinical testing	The p.E383K variant (also known as c.1147G>A), located in coding exon 10 of the NBN gene, results from a G to A substitution at nucleotide position 1147. The glutamic acid at codon 383 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001584263	SCV001811753	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000528325	SCV002044699	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001584263	SCV005623874	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	The NBN c.1147G>A (p.Glu383Lys) variant has not been reported in individuals with NBN-related conditions in the published literature. The frequency of this variant in the general population, 0.000098 (3/30570 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000528325	SCV002078598	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-02-22	no assertion criteria provided	clinical testing