Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589178 | SCV000694417 | pathogenic | Wilson disease | 2024-04-03 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.2294A>G (p.Asp765Gly) results in a non-conservative amino acid change located in the P-type ATPase, subfamily IB domain (IPR027256) of the encoded protein sequence. Another missense change affecting this amino acid has been determined to be pathogenic. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251070 control chromosomes (gnomAD). c.2294A>G has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Wang_2011, Gu_2013, Zhang_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 14986826, 21796144, 24253677, 23843956, 27022412, 35220961). ClinVar contains an entry for this variant (Variation ID: 495406). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV000589178 | SCV000960356 | pathogenic | Wilson disease | 2023-07-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp765 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9482578, 15024742, 20517649, 21682854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 495406). This missense change has been observed in individual(s) with Wilson disease (PMID: 23843956, 30384382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 765 of the ATP7B protein (p.Asp765Gly). |
| 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. |
| Genome- |
RCV000589178 | SCV001977335 | likely pathogenic | Wilson disease | 2021-08-10 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000589178 | SCV005053105 | pathogenic | Wilson disease | 2023-11-20 | criteria provided, single submitter | clinical testing |