ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2333G>T (p.Arg778Leu) (rs28942074)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000389880 SCV000329797 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The R778L variant in the ATP7B gene is one of the most prevalent pathogenic variants reported in the ATP7B gene in Asian populations (Wang et al., 2011; Gu et al., 2013). The R778L variant has been reported previously in numerous individuals with Wilson disease in both the homozygous and compound heterozygous states (Wu et al., 2001; Wang et al., 2011; Gu et al., 2013). The R778L variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R778L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of R778L indicate that while the protein may retain some ability to transport copper (Forbes et al., 1998), R778L may compromise ATP7B function and disrupts the subcellular localization and trafficking of ATP7B protein (Zhu et al., 2015). We interpret R778L as a pathogenic variant.
Myriad Women's Health, Inc. RCV000004056 SCV000485260 pathogenic Wilson disease 2016-02-29 criteria provided, single submitter clinical testing
Invitae RCV000004056 SCV000752250 pathogenic Wilson disease 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 778 of the ATP7B protein (p.Arg778Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs28942074, ExAC 0.2%). This variant is the most common cause of Wilson disease in Asia, having been reported as homozygous in several affected individuals (PMID: 10453196, 11405812, 25086856, 25988284, 27398169, 28212618). ClinVar contains an entry for this variant (Variation ID: 3852). Experimental studies have shown that this missense change leads to ATP7B protein subcellular mislocalization and instability in vitro and is unable to rescue yeast cells null for ATP7B(PMID: 9837819, 10942420, 19937698). A different missense substitution at this codon (p.Arg778Trp) has been determined to be pathogenic (PMID: 11243728, 11479773, 23518715, 17160357, 16998622). 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.
Illumina Clinical Services Laboratory,Illumina RCV000004056 SCV000914629 pathogenic Wilson disease 2017-04-28 criteria provided, single submitter clinical testing The ATP7B c.2333G>T (p.Arg778Leu) variant is widely reported in the literature as a common variant in Wilson disease (WD) in Asian populations. Across a selection of available literature, the p.Arg778Leu variant has been identified in 114 WD patients of Chinese, Japanese, and Korean ancestry, including 32 homozygotes, 57 compound heterozygotes, and 32 heterozygotes. The variant was also found in a heterozygous state in six unaffected parents of probands (Thomas et al. 1995; Kusuda et al. 2000; Wu et al. 2001; Yoo et al. 2002; Bae et al. 2009; Hua et al. 2016, Zong et al. 2016). Wu et al. (2001) found that patients who were homozygous for the p.Arg778Leu variant had an earlier age of onset (14.2 years vs. 22.0 years) and neurologic rather than hepatic symptoms at onset when compared to compound heterozygotes. The p.Arg778Leu variant was absent from 60 controls (Wu et al. 2001), but is reported at a frequency of 0.00232 in the East Asian population of the Exome Aggregation Consortium. Van den Berghe et al. (2009) demonstrated reduced protein expression and mislocalization to the endoplasmic reticulum of the p.Arg778Leu variant protein compared to wild type. Zhu et al. (2015) showed that the p.Arg778Leu variant caused reduced copper excretion and impaired the protective effect of the wild type protein on cell exposed to excess copper. Based on the collective evidence, the p.Arg778Leu variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000004056 SCV000916618 pathogenic Wilson disease 2017-09-14 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2333G>T (p.Arg778Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that lies within the P-type ATPase, transmembrane domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/246194 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been identified in numerous patients as compound heterozygous and homozygous, and multiple other mutations have been reported in patients at the same codon (R778L, R778G, R778Q, and R778W), suggesting the site is a mutational hotspot. Functional studies in yeast showed that copper transport was severely impaired and the variant protein was mislocalized to the ER and/or lysosomes (Forbes_2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV000004056 SCV001163732 pathogenic Wilson disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004056 SCV001194034 pathogenic Wilson disease 2019-12-19 criteria provided, single submitter clinical testing NM_000053.3(ATP7B):c.2333G>T(R778L) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 17587212 and 11405812. Classification of NM_000053.3(ATP7B):c.2333G>T(R778L) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.
OMIM RCV000004056 SCV000024222 pathogenic Wilson disease 2011-09-01 no assertion criteria provided literature only
GeneReviews RCV000004056 SCV000086652 pathologic Wilson disease 2013-05-16 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect, ClinGen RCV000004056 SCV000607168 not provided Wilson disease no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
SingHealth Duke-NUS Institute of Precision Medicine RCV000004056 SCV000853105 pathogenic Wilson disease 2017-06-07 no assertion criteria provided curation

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