Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000672021 | SCV000797076 | likely pathogenic | Wilson disease | 2018-01-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000672021 | SCV003442224 | pathogenic | Wilson disease | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 988 of the ATP7B protein (p.Gly988Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 16283883, 22677543, 24094725, 24668339, 30230192). ClinVar contains an entry for this variant (Variation ID: 556075). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. This variant disrupts the p.Gly988 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30702195). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000672021 | SCV004099925 | likely pathogenic | Wilson disease | 2023-09-18 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.2962G>C (p.Gly988Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248932 control chromosomes. c.2962G>C has been reported in the literature in multiple individuals affected with Wilson Disease, either at a homozygous state or at a compound heterozygous state along with second pathogenic variant(s) (example,Czlonkowska_2018, Gromadzka_2005, Bost_2012, Chabik_2014, Litwin_2014, Capalbo_2019, Ferenci_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, several missense variants at the Gly988 residue have been reported in cases with Wilson Disease (c.2962G>A(p.G988R), c.2963G>A(p.G988E), c.2963G>T(p.G988V)), suggesting that this codon might be functionally important. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22677543, 31589614, 23774950, 29418065, 30232804, 16283883, 24668339). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic, n=1; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000672021 | SCV004216416 | likely pathogenic | Wilson disease | 2023-05-25 | criteria provided, single submitter | clinical testing |