ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2810del (p.Val937fs) (rs1057516643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409795 SCV000485998 likely pathogenic Wilson disease 2016-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000482624 SCV000568296 pathogenic not provided 2016-12-20 criteria provided, single submitter clinical testing The c.2810delT variant in the ATP7B gene has been reported previously in patients with Wilson disease (Wu et al. 2001; Wan et al. 2010). Expression studies found that c.2810delT completely inhibited copper-transporting activity of the ATP7B protein (Wan et al., 2010). The c.2810delT variant was not observed 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. The c.2810delT deletion causes a frameshift starting with codon Valine 937, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Val937GlyfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.2810delT to be a pathogenic variant.
Invitae RCV000409795 SCV000962320 pathogenic Wilson disease 2019-11-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val937Glyfs*5) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 20931554, 26483271). ClinVar contains an entry for this variant (Variation ID: 370632). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000409795 SCV001339143 pathogenic Wilson disease 2020-03-16 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2810delT (p.Val937GlyfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249570 control chromosomes (gnomAD). c.2810delT has been reported in the literature in individuals (homozygous and compound heterozygous) affected with Wilson Disease (e.g. Wan_2010, Hui_2013, Mak_2008). These data indicate that the variant is likely to be associated with disease. In copper resistance assay to determine the effect of the mutation on cell survival, the variant completely inhibited copper-transporting activity as indicated by the rapid death of cells expressing the mutant ATP7B when they were exposed to 20uM copper (Wan_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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