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

gnomAD frequency: 0.00003  dbSNP: rs372979339

Total submissions: 7

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.