ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2292C>T (p.Phe764=)

gnomAD frequency: 0.00003  dbSNP: rs372979339
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000145260 SCV000192323 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Molecular Diagnostics, Microbiology, Virology, Parasitology and Genetics,Sofia University, St. Kliment Ohridski RCV000855544 SCV000920943 likely pathogenic Wilson disease 2019-06-14 criteria provided, single submitter clinical testing The p.Phe764Phe variant in ATP7B has been found in 1 Bulgarian and 1 Egyptian families and was segregated with the disease and associated with low ceruloplasmin levels in carriers for this variant.
Invitae RCV000855544 SCV001064251 likely benign Wilson disease 2021-11-29 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000855544 SCV001368622 uncertain significance Wilson disease 2019-05-08 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2.
Genome-Nilou Lab RCV000855544 SCV001977164 likely benign Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855544 SCV001983633 likely pathogenic Wilson disease 2021-09-21 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2292C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, preliminary reports provided experimental evidence that this might affect mRNA splicing, resulting in partial splice defect, with an in-frame skipping of exon 8 (Wilson_2009, Panzer_2019); in addition, the deletion of exon 8 at the protein level was shown to result in decreased protein level, mislocalization of the shorter protein, and CHO cells expressing ATP7B-delEx8 showed severe inability to tolerate copper (Wilson_2009). The variant allele was found at a frequency of 7.6e-06 in 394326 control chromosomes (gnomAD v2.1 and v3.1 datasets). The variant, c.2292C>T, has been reported earlier in the literature in multiple cohorts of Wilson Disease patients without specifying the genotype (e.g. Todorov_2005, Vrabelova_2005, Dong_2016). However, recently it was also found in several homozygous- and compound heterozygous individuals (with a pathogenic variant in trans), who were affected with Wilson Disease (Singh_2019, Panzer_2019, Collins_2021, Fang_2021). In addition, a recent report based on literature/database reviews, cited the variant in 11 patients affected with Wilson disease, noting that all carried a well-known second variant, and the allele frequency of the variant c.2292C>T was found to be >650-fold higher in this Wilson disease cohort than in public databases (Espinos_2020). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1), VUS (n=1) or Likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV002225450 SCV002504433 likely benign not provided 2018-11-29 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.

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