ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2294A>G (p.Asp765Gly) (rs1555291147)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589178 SCV000694417 pathogenic Wilson disease 2016-04-08 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2294A>G variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was not observed in controls (1000 Gs, ESP, or ExAC). Multiple publications cite the variant in affected individuals and authors indicate the variant is located in the predicted transmembrane helical hairpin N-terminal to the transduction domain, therefore it is predicted to be important for proper protein function (Gu_2003). Multiple publications and a database cite the variant to be "pathogenic/disease variant." In addition, another variant affecting this amino acid, c.2293G>A, p.Asp765Asn has been reported as a pathogenic variant. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000589178 SCV000960356 likely pathogenic Wilson disease 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 765 of the ATP7B protein (p.Asp765Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ATP7B variant in an individual affected with Wilson disease (PMID: 23843956). ClinVar contains an entry for this variant (Variation ID: 495406). 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. This variant disrupts the p.Asp765 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21682854, 15024742, 9482578, 20517649), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589178 SCV001159920 likely pathogenic Wilson disease 2018-08-27 criteria provided, single submitter clinical testing The ATP7B c.2294A>G; p.Asp765Gly variant is reported in the literature in multiple individuals affected with Wilson disease and has been observed in trans to another pathogenic ATP7B variant in several affected individuals (Gu 2003, Gu 2013, Wang 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 495406), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant at this codon (p.Asp765Asn) has been reported in individuals with Wilson disease and is considered pathogenic (Figus 1995, Kalinsky 1998), consistent with functional assays that indicate aberrant localization and decreased transport activity (Forbes 2000, Huster 2012). The aspartate at codon 765 is highly conserved and both computational analyses (SIFT, PolyPhen-2) and structural modeling approaches predict that the p.Asp765Gly variant is deleterious (Schushan 2012, Squitti 2014). Based on available information, this variant is considered to be likely pathogenic. References: Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995 Dec;57(6):1318-24. Forbes JR and Cox DW. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet. 2000 Aug 12;9(13):1927-35. 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. Gu YH et al. Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet. 2003 Dec;64(6):479-84. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. Schushan M et al. A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. Metallomics. 2012 Jul;4(7):669-78. Squitti R et al. In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure. Biometals. 2014 Feb;27(1):53-64. Wang LH et al. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet. 2011 Sep;56(9):660-5.

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