ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.4058G>A (p.Trp1353Ter) (rs193922110)

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Total submissions: 5
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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 RCV000029378 SCV000052026 pathogenic Wilson disease 2021-02-17 criteria provided, single submitter clinical testing Variant summary: ATP7B c.4058G>A (p.Trp1353X) 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. At-least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 247964 control chromosomes. c.4058G>A has been reported in the literature in at-least one individual affected with Wilson Disease and subsequently cited by others (example, Curtis_1999 and Coffey_2003, Li_2012, Singh_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 (n=2)/likely pathogenic (n=1). One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000029378 SCV000220454 likely pathogenic Wilson disease 2014-06-25 criteria provided, single submitter literature only
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415977 SCV000493528 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000415977 SCV000748221 likely pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing The W1353X variant in the ATP7B gene has been reported previously in association with Wilson disease, however it was identified in a single allele among a cohort of unrelated affected patients without information about zygosity (Curtis et al., 1999). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W1353X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret W1353X as a likely pathogenic variant.
Invitae RCV000029378 SCV000836786 pathogenic Wilson disease 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1353*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs193922110, ExAC 0.002%). This variant has been observed in an individual affected with Wilson disease (PMID: 10502777). ClinVar contains an entry for this variant (Variation ID: 35729). 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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