Description
Variant summary: ATP7B c.1922T>C (p.Leu641Ser) 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 allele was found at a frequency of 0.0005 in 251632 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0005 vs 0.0054), allowing no conclusion about variant significance. The variant c.1922T>C has been reported in the literature in individuals affected with Wilson Disease (example: Cox_2005, Vrabelova_2005, Bost_2012, Ferenci_2019), however, in most of these cases no full gene sequencing was performed, and/or the other pathogenic variant in trans was not specified and/or phase was not provided. These data therefore do not allow clear conclusions about the variant significance. Publications also reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein localization, copper transport activity, and copper-responsive trafficking (Braiterman_2014) and no effect on interaction with COMMD1 (de Bie_2007). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
