ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2905C>T (p.Arg969Trp) (rs774028495)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434557 SCV000520884 likely pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000780936 SCV000918601 likely pathogenic Wilson disease 2018-07-23 criteria provided, single submitter clinical testing 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.
Counsyl RCV000780936 SCV001132128 uncertain significance Wilson disease 2019-01-24 no assertion criteria provided clinical testing

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