ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1934T>G (p.Met645Arg) (rs121907998)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000004066 SCV000052000 pathogenic Wilson disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000004066 SCV000192314 pathogenic Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000004066 SCV000384672 pathogenic Wilson disease 2016-06-14 criteria provided, single submitter clinical testing Across a selection of available literature, the c.1934T>G (p.Met645Arg) variant has been identified in a compound heterozygous state in at least 23 patients with Wilson disease (Shah et al. 1997; Kalinsky et al. 1998; Deguti et al. 2004; Margarit at al. 2005). The p.Met645Arg variant was absent from 195 controls but is reported at a frequency of 0.00285 in the Latino population of the Exome Aggregation Consortium. The p.Met645Arg variant results in a change of a neutral nonpolar residue to a basic residue. The variant is located in trans-membrane region 1, hence this substitution is expected to disrupt the structure of the transmembrane domain. Functional studies in Sf9 cells demonstrated that the variant displayed copper uptake activity that was indistinguishable from wild type, however the variant was hyperphosphorylated compared to wild type ATP7B (Huster et al. 2012). Studies in SV40-transformed ATP7A-null cells also showed that the p.Met645Arg variant and other missense variants do not disrupt copper transport activity (Braiterman et al. 2014). The biochemical defect for this variant therefore remains to be elucidated. Based on the clinical evidence from the literature, the p.Met645Arg variant is classified as pathogenic for Wilson disease.
Fulgent Genetics,Fulgent Genetics RCV000004066 SCV000611173 pathogenic Wilson disease 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000004066 SCV000626834 pathogenic Wilson disease 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 645 of the ATP7B protein (p.Met645Arg). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs121907998, ExAC 0.3%). This variant has been reported as homozygous or compound heterozygous in many individuals affected with Wilson disease (PMID: 15952988, 11093740, 9482578, 9671269, 9311736, 21832955, 19118915). ClinVar contains an entry for this variant (Variation ID: 3862). Experimental studies have reported conflicting results for impact of this missense change on protein function, with some reports suggesting no impact on ATP7B activity (PMID: 9311736, 22240481), and a report indicating a mild decrease in ATP7B copper transport (PMID: 9311736). Although functional studies report conflicting data for the impact of this missense change on ATP7B function, it has been reported in many individuals with Wilson disease. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000004066 SCV000678054 likely pathogenic Wilson disease 2015-04-28 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000004066 SCV000803476 uncertain significance Wilson disease 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Wilson disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3-Strong => Recessive disorder and variant detected in trans with pathogenic variant in multiple patients. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:17919502) (PMID:24706876,22240481).
OMIM RCV000004066 SCV000024232 pathogenic Wilson disease 2005-07-01 no assertion criteria provided literature only

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