ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.503G>A (p.Gly168Glu) (rs1554566728)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559552 SCV000634314 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 168 of the NBN protein (p.Gly168Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an NBN-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on NBN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764787 SCV000895931 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023458 SCV001185338 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001192404 SCV001360499 uncertain significance not specified 2019-08-13 criteria provided, single submitter clinical testing Variant summary: NBN c.503G>A (p.Gly168Glu) results in a non-conservative amino acid change located in the BRCT domain (IPR036420) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251246 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.503G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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