ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2184+1G>T (rs756363734)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222999 SCV000277794 likely pathogenic Hereditary cancer-predisposing syndrome 2015-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000411514 SCV000486752 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2016-08-04 criteria provided, single submitter clinical testing
GeneDx RCV000478822 SCV000571724 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted NBN c.2184+1G>T or IVS14+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 14 of the NBN gene. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant and was not observed at a significant allele frequency in large population cohorts (Lek 2016). Canonical splice variants are typically expected to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, this variant is predicted to result in an in-frame deletion of an exon comprising 38 amino acids, 37 of which are not located in a known functional domain and may not cause loss of normal protein function. In the absence of RNA or functional studies, the actual effect of this variant is unknown. Thus, we consider NBN c.2184+1G>T to be a variant of uncertain significance.
Invitae RCV000411514 SCV000553125 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-08-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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: 233424). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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