ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2332C>T (p.Arg778Trp) (rs137853284)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532036 SCV000626843 pathogenic Wilson disease 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 778 of the ATP7B protein (p.Arg778Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137853284, ExAC 0.01%). This variant has been reported as homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 11243728, 11479773, 23518715, 17160357, 16998622). This variant has been observed in an individual with Kayser-Fleischer rings and low serum ceruloplasmin, findings that are highly specific for Wilson disease (PMID: 17160357). 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. Different missense substitutions at this codon (p.Arg778Leu, p.Arg778Gly and p.Arg778Glu) have been determined to be pathogenic (PMID: 19937698, 10790207, 23333878, 21682854, 20517649, 16283883, 20931554, 27022412, 11405812). This suggests that the arginine residue is critical for ATP7B protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000532036 SCV000694420 pathogenic Wilson disease 2017-03-09 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2332C>T (p.Arg778Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/120374 control chromosomes at a frequency of 0.0000415, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant is in the P-type ATPase A domain (IPR008250) with one study (Kumar_MCB_2007) showing decreased copper stimulated ATPase activity with this variant compared to WT and biochemical finding suggesting deleterious effect (Kumar, 2007; Dufernez, 2013). The variant was identified in multiple affected individuals homozygously or in compound heterozygosity in patients with clinically and biochemically confirmed Wilsons disease (WD). Multiple family studies showed segregation of this variant with WD. The codon Arg778 appears to be a mutational hot-spot, as other alteration, such as p.R778Q, p.R778G and p.R778L have been reported in patients with WD. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000532036 SCV001157899 pathogenic Wilson disease 2018-09-25 criteria provided, single submitter clinical testing The ATP7B c.2332C>T; p.Arg778Trp variant (rs137853284) is reported in the homozygous and compound heterozygous state in several individuals with Wilson disease (WD, Butler 2001, Coffey 2013, Kumar 2007, Shah 1997) and is described as segregating with disease (Coffey 2013). The variant is listed in the ClinVar database (Variation ID: 456553) and in the general population with an overall allele frequency of 0.005% (13/246100 alleles) in the Genome Aggregation Database. The arginine at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. In support of this prediction, this variant has been shown to have reduced function (Kumar 2007). Additionally, other variants at this codon (p.Arg778Gln, p.Arg778Gly, p.Arg778Leu) have been reported in individuals with WD and are considered pathogenic (Dong 2016, Forbes 1998, Kumar 2007, Schushan 2012). Considering available information, this variant is classified as pathogenic. References: Butler P et al. Molecular diagnosis of Wilson disease. Mol Genet Metab. 2001 Mar;72(3):223-30. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. 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. Forbes JR and Cox DW. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet. 1998 Dec;63(6):1663-74. Kumar S et al. Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: correlation between genotype/phenotype/copper ATPase activity. Mol Cell Biochem. 2007 Jan;294(1-2):1-10. 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. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28.
Baylor Genetics RCV000532036 SCV001163733 pathogenic Wilson disease criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091641 SCV001247801 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Counsyl RCV000532036 SCV001132125 pathogenic Wilson disease 2014-01-02 no assertion criteria provided clinical testing

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