Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000053.4(ATP7B):c.3664dupG(p.Asp1222GlyfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]
ATP7B Gene-Disease associations (from GenCC):
Wilson disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-51939085-T-TC is Pathogenic according to our data. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939085-T-TC is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1415202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
This sequence change creates a premature translational stop signal (p.Asp1222Glyfs*37) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP7B-related conditions. For these reasons, this variant has been classified as Pathogenic. -