ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.2731-2A>G (rs367956522)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169025 SCV000220173 likely pathogenic Wilson disease 2014-03-20 criteria provided, single submitter literature only
GeneDx RCV000485754 SCV000568297 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing The c.2731-2A>G pathogenic variant in the ATP7B gene has been reported previously in the homozygous state in association with Wilson disease (Shah et al., 1997). This splice site variant destroys the canonical splice acceptor site in intron 11. Sequencing of mutant APT7B RNA shows exon 12 skipping as well as an insertion of 13 amino acids, due to the use of a cryptic splice acceptor site (Shah et al., 1997). The c.2731-2A>G variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2731-2A>G as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000169025 SCV000694427 pathogenic Wilson disease 2016-07-19 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2731-2A>G variant located at a conserved intronic position, known to affect splicing with 5/5 splice prediction tools predicting a significant effect on splicing, which has been functionally supported (Shah_1997). This mutation produces 13 additional amino acids (VVISHGLGVLFSW) in the region between the transduction motif and the fifth Tm region. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/119818 (1/59909), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/185. Multiple publications cite the variant in affected individuals including a homozygous individual, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000169025 SCV000825192 pathogenic Wilson disease 2018-06-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the ATP7B 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 (rs367956522, ExAC 0.009%). This variant has been observed as homozygous and in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 9311736, 23518715, Invitae). ClinVar contains an entry for this variant (Variation ID: 188725). Experimental studies have shown that this splice acceptor change disrupts splicing resulting in skipping exon 12 or the usage of a cryptic splice site and the insertion of 13 additional amino acids (PMID: 9311736). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.

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