ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.19_20del (p.Gln7fs) (rs749363958)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478984 SCV000567525 uncertain significance not provided 2021-02-19 criteria provided, single submitter clinical testing Reported homozygous in a female pediatric patient with no symptoms of Wilson disease or abnormalities on liver biopsy (Stalke et al., 2019); Expression of mRNA in liver cells of a patient homozygous for the variant was in the range of healthy controls and in-vitro expression assays found mRNA and protein levels comparable to wild type, suggesting that the variant may bypass nonsense-mediated mRNA decay (NMD) allowing normal copper export (Stalke et al., 2019); This variant is associated with the following publications: (PMID: 18371106, 30291343, 26752957, 15967699, 30723317, 29649982, 31169307, 23486543, 31980526)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000478984 SCV000602607 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing
Counsyl RCV000576360 SCV000678019 uncertain significance Wilson disease 2017-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175369 SCV000918583 uncertain significance not specified 2019-11-08 criteria provided, single submitter clinical testing Variant summary: ATP7B c.19_20delCA (p.Gln7AspfsX14) 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 (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. However, a functional study (Stalke_2019) found the variant mRNA and protein is expressed in size and amount comparable to wild-type while, copper export capacity was also comparable to wild-type; these results indicating that c.19_20del in ATP7B is able to bypass NMD by translation reinitiation. The variant allele was found at a frequency of 0.00015 in 249432 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.19_20delCA has been reported in the literature in individuals affected with Wilson Disease, however, with limited information (i.e. second mutation not being provided) (Vrabelova_2005). In addition, multiple individuals, one compound heterozygote adult (Loudianos_2016) and one homozygous adolescent (Stalke_2019), were found to be asymptomatic. These reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. Four ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000576360 SCV000939965 pathogenic Wilson disease 2020-09-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln7Aspfs*14) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs749363958, ExAC 0.03%). This variant has been observed in an individual affected with Wilson disease (PMID: 15967699). ClinVar contains an entry for this variant (Variation ID: 419611). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000478984 SCV001149058 likely pathogenic not provided 2016-12-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000576360 SCV001163740 likely pathogenic Wilson disease criteria provided, single submitter clinical testing

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