Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000796453 | SCV000935967 | pathogenic | Wilson disease | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 888 of the ATP7B protein (p.Thr888Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 23843956, 27398169). ClinVar contains an entry for this variant (Variation ID: 642900). 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%. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV000796453 | SCV001473539 | likely pathogenic | Wilson disease | 2021-10-11 | criteria provided, single submitter | clinical testing | The ATP7B c.2662A>C; p.Thr888Pro variant (rs1455758826) is reported in the literature in several individuals with Wilson disease and many were reported to carry an additional pathogenic ATP7B variant presumably in trans (Chen 2019, Gu 2013, Hua 2016, Li 2011, Mak 2008, Xiao 2019). The p.Thr888Pro variant is reported in ClinVar (Variation ID: 642900). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 888 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.934). Based on available information, the p.Thr888Pro variant is considered to be likely pathogenic. References: Chen YC et al. Contribution of intragenic deletions to mutation spectrum in Chinese patients with Wilson's disease and possible mechanism underlying ATP7B gross deletions. Parkinsonism Relat Disord. 2019 May;62:128-133. PMID: 30655162. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. PMID: 23843956. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. PMID: 27398169. Li XH et al. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. BMC Med Genet. 2011 Jan 11;12:6. PMID: 21219664. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. Epub 2007 Nov 22. PMID: 18034201. Xiao H et al. Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease. Digestion. 2019;99(4):319-326. PMID: 30384382. |
| Genome- |
RCV000796453 | SCV001977310 | likely pathogenic | Wilson disease | 2021-08-10 | criteria provided, single submitter | clinical testing |