ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.994+1G>T

dbSNP: rs1554562083
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000553121 SCV000634348 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2024-04-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the NBN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 461594). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000755042 SCV000882862 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000755042 SCV001181336 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-25 criteria provided, single submitter clinical testing The c.994+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the NBN gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
GeneDx RCV003328595 SCV004035625 likely pathogenic not provided 2023-09-15 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16199547, 16415040, 9590180)
Baylor Genetics RCV003459221 SCV004191980 likely pathogenic Aplastic anemia 2023-11-14 criteria provided, single submitter clinical testing

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