ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2662A>C (p.Thr888Pro) (rs1455758826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000796453 SCV000935967 pathogenic Wilson disease 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 888 of the ATP7B protein (p.Thr888Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ATP7B variant in several individuals affected with Wilson disease (PMID: 23843956, 27398169). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000796453 SCV001473539 likely pathogenic Wilson disease 2019-09-30 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 (SIFT, PolyPhen-2) predict that this variant is deleterious. 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. 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. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. 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. 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. Xiao H et al. Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease. Digestion. 2019;99(4):319-326.

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