ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2333G>A (p.Arg778Gln) (rs28942074)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665805 SCV000789984 pathogenic Wilson disease 2017-04-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000665805 SCV000918605 pathogenic Wilson disease 2018-11-28 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2333G>A (p.Arg778Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247080 control chromosomes (gnomAD and publications). c.2333G>A has been reported in the literature in multiple individuals affected with Wilson Disease (Cheng_2017, Dong_2016, Lu_2014, Mukherjee_2014, Wan_2010, Lepori_2007, Park_2007, Wu_2001, Chuang_1996). Individuals who are homozygous for the variant have been reported to present with neurological and hepato-neurological symptoms (Wan_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence indicate a damaging impact of the variant on protein function; specifically, the variant caused reduced copper bound holo-Fet3p activity in ccc2 mutant yeast and only partially rescued mutant yeast in complementation assay (Forbes_1998). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Additionally, a different variant at the same nucleotide and codon position has been described as a common pathogenic variant associated with Wilson disease (c.2333G>T, p.Arg778Leu), especially in the Asian population, supporting the functional importance of this position. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000665805 SCV001402302 pathogenic Wilson disease 2019-09-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 778 of the ATP7B protein (p.Arg778Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs28942074, ExAC 0.03%). This variant has been observed in several individual(s) affected with Wilson disease (PMID: 20931554, 27022412, 11405812, 21796144). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550914). This variant has been reported to affect ATP7B protein function (PMID: 9837819). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 20517649, 21682854, 23333878, 11243728, 11479773, 23518715, 17160357, 16998622, 10453196, 11405812, 25086856, 25988284, 27398169, 28212618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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