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 pathogenic Wilson disease 2022-10-22 criteria provided, single submitter clinical testing This sequence change affects codon 764 of the ATP7B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATP7B protein. This variant is present in population databases (rs372979339, gnomAD 0.004%). This variant has been observed in individual(s) with Wilson disease (PMID: 31059521, 33640437, 33763395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157937). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic.
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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