ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1707+2dup (rs781531824)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000804210 SCV000944106 uncertain significance Wilson disease 2018-07-26 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs781531824, ExAC 0.001%). This variant has been observed in an individual affected with Wilson disease, but no second allele was reported (PMID: 9801873). This variant is also known as c.1703+3insT in the literature. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000804210 SCV001158412 likely pathogenic Wilson disease 2019-04-19 criteria provided, single submitter clinical testing The ATP7B c.1707+2dupT variant (rs781531824), reported as c.1707+3dupT (Loudianos 1998, Loudianos 2002), is reported in the literature in individuals affected with Wilson disease (Curtis 1999, Loudianos 1998). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 4, which is likely to negatively impact gene function, and in vitro functional analyses demonstrate skipping of exon 4 from patient samples (Loudianos 2002). Based on available information, this variant is considered to be likely pathogenic. References: Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. Loudianos G et al. Haplotype and mutation analysis in Greek patients with Wilson disease. Eur J Hum Genet. 1998 Sep-Oct;6(5):487-91. Loudianos G et al. Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. Hum Mutat. 2002 Oct;20(4):260-6.

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