ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3263T>A (p.Leu1088Ter) (rs753250853)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169240 SCV000220514 likely pathogenic Wilson disease 2014-07-16 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169240 SCV001159924 pathogenic Wilson disease 2018-08-30 criteria provided, single submitter clinical testing The ATP7B c.3263T>A; p.Leu1088Ter variant (rs753250853) has been described in several individuals with Wilson disease (Coffey 2013, Deguti 2004, Merle 2010, Vrabelova 2005). It contains an entry in ClinVar (Variation ID: 188886) and observed on only 2 alleles in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Merle U et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 2010 Jan 18;10:8. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85.
Invitae RCV000169240 SCV001403793 pathogenic Wilson disease 2020-09-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1088*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753250853, ExAC 0.002%). This variant has been observed in individuals affected with Wilson disease (PMID: 15024742, 23518715,12515040, 20082719). ClinVar contains an entry for this variant (Variation ID: 188886). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169240 SCV001737902 pathogenic Wilson disease 2021-06-14 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3263T>A (p.Leu1088X) 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 8e-06 in 249552 control chromosomes. c.3263T>A has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Deguti_2004, Vrabelova_2005, Merle_2010, Sanchez-Monteagudo_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001557295 SCV001779030 pathogenic not provided 2020-11-20 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32043565, 25497208, 15024742, 20517649, 20082719, 12515040, 25525159)

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