ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3061-12T>A (rs1045194246)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673212 SCV000798390 likely pathogenic Wilson disease 2018-03-08 criteria provided, single submitter clinical testing
Mendelics RCV000673212 SCV001139352 pathogenic Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000673212 SCV001482032 pathogenic Wilson disease 2021-02-20 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3061-12T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site. Two predict the variant weakens a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Loudianos_2002). The variant allele was found at a frequency of 4.1e-06 in 245682 control chromosomes. c.3061-12T>A has been reported in the literature in multiple individuals affected with Wilson Disease (example, Loudianos_2012, Silva_2011, Bost_2012, Dufernez_2013, Sanchez-Monteagudo_2020). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. One submitter has cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000673212 SCV001590618 pathogenic Wilson disease 2020-09-21 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 12325021, 22687675, 23567103). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557116). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 12325021). For these reasons, this variant has been classified as Pathogenic.

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