ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1946+6T>C (rs751287778)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588787 SCV000694408 likely pathogenic Wilson disease 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.1946+6T>C variant involves the alteration of a conserved intronic nucleotide. 3/5 splice prediction tools via Alamut suggest potential impact on a normal splicing pattern, which was confirmed by the RNA studies performed on RNA extracted from peripheral lymphoblasts and liver cells from a homozygous pt. Based on the results, c.1946+6T>C leads to an alternative transcript that is lacking exons 6,7,8 (Zappu_MCP_2012). The variant is present in the large control population dataset of ExAC at a very low frequency 0.0000084 (1/120708 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant in ATP7B gene (0.0054). The variant of interest has been reported in affected individuals with clinically and biochemically confirmed dx of WD via published reports. Taken together, this variant is classified as Likely Pathogenic.
Counsyl RCV000588787 SCV000799146 uncertain significance Wilson disease 2018-04-05 criteria provided, single submitter clinical testing
Invitae RCV000588787 SCV001575736 likely pathogenic Wilson disease 2020-07-30 criteria provided, single submitter clinical testing This sequence change falls in intron 6 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 (rs751287778, ExAC 0.001%). This variant has been observed to be homozygous in an individual affected with Wilson disease (PMID: 22019423). ClinVar contains an entry for this variant (Variation ID: 495403). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22019423). 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.

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