ClinVar Genomic variation as it relates to human health

The R969W missense variant has been reported previously in patients with Wilson disease (Lepori et al. 2007; Dong et al. 2016). The R969W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R969W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A missense variants in the same residue (R969Q) has been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret R969W to be a likely pathogenic variant.

Variant summary: ATP7B c.2905C>T (p.Arg969Trp) results in a non-conservative amino acid change located in the Transmembrane 6 domain of 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 4.3e-05 in 277302 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.3e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.2905C>T, has been reported in the literature in individuals affected with Wilson Disease with limited information (ie, lack of genotypic information, co-occurrence and/or cosegregation)(Dong_2016, Lepori_2007, Li_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, reputable databases (Alberta University) and a ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic". In addition, another variant affecting the same codon, Arg969Gln, has been reported in affected individuals and classified as pathogenic indicating that the location may be a hotspot. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 969 of the ATP7B protein (p.Arg969Trp). This variant is present in population databases (rs774028495, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 27022412, 34470610, 35220961). ClinVar contains an entry for this variant (Variation ID: 381534). 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) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. This variant disrupts the p.Arg969 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8533760, 15523622). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces arginine with tryptophan at codon 969 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 17949296, 27022412, 34470610). This variant has been identified in 12/280866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg969Gln, is a well documented pathogenic mutation (ClinVar Variation ID: 3860), indicating that arginine at this position is important for ATP7B protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.