ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.481-2A>T (rs751567476)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569604 SCV000662681 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000569604 SCV000690722 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000523496 SCV000619808 likely pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted NBN c.481-2A>T or IVS4-2A>T and consists of an A>T nucleotide substitutionat the -2 position of intron 4 of the NBN gene. This variant destroys a canonical splice acceptor site and is predicted tocause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature.Based on the currently available information, we consider NBN c.481-2A>T to be a likely pathogenic variant
Integrated Genetics/Laboratory Corporation of America RCV000707500 SCV000919849 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-03-12 criteria provided, single submitter clinical testing Variant summary: NBN c.481-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 245872 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (1.2e-05 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.481-2A>T in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000707500 SCV000836601 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs751567476, ExAC 0.002%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 451148). 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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