ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1816G>A (p.Glu606Lys) (rs774324419)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166446 SCV000217242 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000586042 SCV000697956 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The c.1816G>A (p.Glu606Lys) in NBN gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present at a low frequencies in the control population datasets of ExAC and gnomAD (8.24e-06; 1/121362 and 2/245612 chrs tested, respectively). These frequencies do not exceed the maximal expected allele frequency for a disease causing allele in NBN gene (0.000125). To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Invitae RCV000636773 SCV000758214 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 606 of the NBN protein (p.Glu606Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs774324419, ExAC 0.001%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 186796). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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