ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2605G>A (p.Gly869Arg) (rs191312027)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145263 SCV000192329 pathogenic Wilson disease 2013-06-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413599 SCV000337715 pathogenic not provided 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000413599 SCV000490419 pathogenic not provided 2016-06-10 criteria provided, single submitter clinical testing The G869R pathogenic variant in the ATP7B has been previously reported in association with Wilson disease (Shah et al., 1997: Margarit et al., 2005). It was reported in two compound heterozygotes both with hepatic disease; one also had severe Parkinsonism (Margarit et al., 2005). In vitro studies found this variant is associated with decreased phosphatase activity (Shah et al., 1997). Therefore we consider G869R to be a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000145263 SCV000584069 likely pathogenic Wilson disease 2015-02-10 criteria provided, single submitter research
Invitae RCV000145263 SCV000626844 likely pathogenic Wilson disease 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 869 of the ATP7B protein (p.Gly869Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs191312027, ExAC 0.1%). This variant has been reported to be compound heterozygous in several individuals affected with Wilson disease (PMID: 23843956, 15952988, 27398169, 11093740). ClinVar contains an entry for this variant (Variation ID: 157939). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000145263 SCV000694426 pathogenic Wilson disease 2019-03-01 criteria provided, single submitter clinical testing Variant summary: The variant, ATP7B c.2605G>A (p.Gly869Arg) results in a non-conservative amino acid change in 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 0.00072 in 280222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00072 vs 0.0054), allowing no conclusion about variant significance. The variant is reported in numerous affected individuals without K-F rings in the literature, reported in late-onset patients with mild phenotype, and in some cases, in clinically asymptomatic individuals, although with abnormal biochemical findings (low plasma Cu and CP levels, elevated urinary Cu level). Therefore, this variant represents a mild mutation with a phenotypic outcome significantly dependent on a genetic background (Dong_2016, Ferenci_2007, Gu_2013, Mukherjee_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely Pathogenic X5) and uncertain significance X1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000623574 SCV000741467 uncertain significance Inborn genetic diseases 2017-07-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000145263 SCV000885048 pathogenic Wilson disease 2018-09-05 criteria provided, single submitter clinical testing The ATP7B c.2605G>A; p.Gly869Arg variant (rs191312027) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease, some of whom also carried an additional pathogenic variant (Dong 2016, Gu 2013, Hua 2016, Margarit 2005, Mukherjee 2014). The variant is described in ClinVar database as pathogenic by several sources (Variation ID: 157939). This variant is found in the European population with an overall allele frequency of 0.1% (159/126726 alleles) in the Genome Aggregation Database. The glycine at codon 869 is highly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. 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. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000145263 SCV000966821 likely pathogenic Wilson disease 2018-07-18 criteria provided, single submitter clinical testing The p.Gly869Arg variant in ATP7B has been reported 5 individuals with Wilson dis ease, all of whom were compound heterozygous (Garcia-Villarreal 2000, Margarit 2 005, Gu 2013, Hua 2016). This variant has also been reported in ClinVar (Variati on ID#3848). This variant has also been identified in 0.125% (159/126726) of Eur opean chromosomes by Genome Aggregation Database (gnomAD, Http://gnomad.broadins titute.org; dbSNP rs191312027). This frequency is consistent with the known carr ier frequency of Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, t he p.Gly869Arg variant is likely pathogenic for Wilson disease in an autosomal r ecessive manner. ACMG/AMP Criteria applied: PM3_Strong; PM2_Supporting; PP3.
Baylor Genetics RCV000145263 SCV001163731 likely pathogenic Wilson disease criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413599 SCV001247799 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing

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