ClinVar Miner

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

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Total submissions: 11
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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 2020-01-08 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.
SIB Swiss Institute of Bioinformatics RCV000004066 SCV000803476 likely pathogenic Wilson disease 2020-04-27 criteria provided, single submitter curation This variant is interpreted as likely pathogenic for Wilson disease, autosomal recessive. NM_000053.4:c.1934T>G has been identified in a compound heterozygous state in multiple patients with Wilson disease (for example PMID:9482578, 9671269, 11093740, 15952988, 17949296), and is present in gnomAD at a frequency compatible with disease prevalence. Functional studies have been published, but results are contradictory. Some studies (PubMed:17919502, 24706876, 22240481) show that the variant has no functional effect. Merico et al. (PubMed:32284880) demonstrate that NM_000053.4:c.1934T>G causes 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, and reduced protein expression. The following ACMG Tag(s) were applied to variant interpretation: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3-Very Strong => For recessive disorders, detected in trans with a pathogenic variant. Criterion has been upgraded because the variant has been detected in multiple patients.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000004066 SCV001159371 pathogenic Wilson disease 2018-10-09 criteria provided, single submitter clinical testing The ATP7B c.1934T>G; p.Met645Arg variant (rs121907998) has been reported in numerous individuals with Wilson disease who were compound heterozygous with another pathogenic variant (Coffey 2013, Deguti 2004, Garcia-Villarreal 2000, Kalinsky 1998, Loudianos 1998, Margarit 2005, Shah 1997). One study of a Spanish Wilson disease cohort observed this variant in 55% of affected individuals (Margarit 2005). This variant is reported as pathogenic in the ClinVar database (Variation ID: 3862) and is found in the general population with an overall allele frequency of 0.05% (134/277206 alleles) in the Genome Aggregation Database. Functional studies show the variant protein becomes hyperphosphorylated but otherwise has similar copper uptake activity as wild type ATP7B protein (Braiterman 2014, Huster 2012); therefore, the disease-causing mechanism of this variant is unclear. However, based on available information, including its prevalence in affected individuals, the p.Met645Arg variant is considered pathogenic. References: Braiterman LT et al. Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):E1364-73. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Garcia-Villarreal L et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology. 2000 Dec;32(6):1329-36. 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. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. 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. 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 RCV000004066 SCV001163736 pathogenic Wilson disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004066 SCV001194140 likely pathogenic Wilson disease 2019-12-17 criteria provided, single submitter clinical testing NM_000053.3(ATP7B):c.1934T>G(M645R) is classified as likely pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 23962630, 19118915, 23518715, 22240481 and 15952988. Classification of NM_000053.3(ATP7B):c.1934T>G(M645R) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000004066 SCV001251517 likely pathogenic Wilson disease criteria provided, single submitter research The ATP7B c.1934T>G (p.M645R) variant has previously been reported in the homozygous and compound heterozygous state in individuals with Wilson disease (PMID: 11093740; 9482578; 9671269; 15952988; 19118915; 20301685).
OMIM RCV000004066 SCV000024232 pathogenic Wilson disease 2005-07-01 no assertion criteria provided literature only

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