ClinVar Miner

Submissions for variant NM_001081.3(CUBN):c.6125-2A>G (rs75386064)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000625652 SCV000746155 likely pathogenic Megaloblastic anemia due to inborn errors of metabolism 2017-10-09 no assertion criteria provided clinical testing
GeneDx RCV000428188 SCV000535408 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing The c.6125-2A>G variant in the CUBN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 40. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although not reported in the homozygous state, the c.6125-2A>G variant was observed at a frequency of 0.61%, 27/4406 alleles, in individuals of African American ancestry by the NHLBI Exome Sequencing Project. We interpret c.6125-2A>G as a variant of uncertain significance.
Invitae RCV000625652 SCV000943786 uncertain significance Megaloblastic anemia due to inborn errors of metabolism 2018-10-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 40 of the CUBN 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 (rs75386064, ExAC 0.8%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CUBN-related disease. ClinVar contains an entry for this variant (Variation ID: 392184). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189). 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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