ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.925G>A (p.Glu309Lys) (rs587780101)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588924 SCV000149716 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing This variant is denoted NBN c.925G>A at the cDNA level, p.Glu309Lys (E309K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Glu309Lys was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Glu309Lys is located in the BRCT2 domain (Damiola 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether NBN Glu309Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214503 SCV000276266 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or Conflicting Evidence,Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000588924 SCV000697983 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The NBN c.925G>A (p.Glu309Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121330 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000636751 SCV000758192 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 309 of the NBN protein (p.Glu309Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 127881). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000214503 SCV000911524 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing

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