ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1877G>C (p.Gly626Ala) (rs587783299)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000145253 SCV000192312 pathogenic Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000145253 SCV000220323 likely pathogenic Wilson disease 2014-05-15 criteria provided, single submitter literature only
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415842 SCV000493244 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000415842 SCV000589556 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The G626A variant has been reported previously in individuals with Wilson disease. It is unknown if these individuals harbor another variant in the ATP7B gene (Figus et al., 1995; Shah et al., 1997; Todorov et al., 2005). Multiple functional studies revealed that G626A resulted in similar copper transport activity to wild-type (Hsi et al., 2008; Huster et al., 2012; Braiterman et al., 2014). The G626A variant is observed in 8/66728 (0.012%) alleles from individuals of European (non-Finnish) background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G262A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000145253 SCV000694406 likely pathogenic Wilson disease 2019-07-03 criteria provided, single submitter clinical testing Variant summary: ATP7B c.1877G>C (p.Gly626Ala) results in a non-conservative amino acid change located in the Heavy metal-associated domain, copper ion-binding (IPR006122) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 249616 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.1877G>C has been reported in the literature, in certain occasions in compound heterozygosity with other pathogenic variants (e.g. p.Gly1061Glu, p.His1069Gln), in multiple individuals affected with Wilson Disease (Bost_2012, Braiterman_2014, Coffey_2013, Figus_1995, Ljubic_2016, Loudianos_1999, Todorov_2005). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function provided conflicting conclusions about the variant effect. Specifically, one study demonstrated the variant to cause partial copper transport activity but normal phosphorylation activity (Huster_2012) while, other studies revealed normal copper transport and trafficking (Braiterman_2014, Hsi_2008). A separate study showed the variant protein retained its ability to interact with COMMD1 but at decreased efficiency (deBie_2007); however, it is not conclusively established if and how this change could lead to disease. Three ClinVar submitters (evaluation after 2014) cite the variant once as likely pathogenic and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic until additional data becomes available to conclusively determine the effect of this variant.
Invitae RCV000145253 SCV000832093 likely pathogenic Wilson disease 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 626 of the ATP7B protein (p.Gly626Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs587783299, ExAC 0.01%). This variant co-occurs with a pathogenic variant in ATP7B in an individual with a ATP7B-related disease (Invitae). Manual review of the sequencing data indicate these two variants are on opposite chromosomes (in trans), which suggests the c.1877G>C substitution may contribute to disease. This variant has been reported in individuals affected with Wilson disease (PMID: 8533760, 22735241, 18371106, 8938442, 16207219, 22677543). This variant is also known as p.Gly627Ala in the literature. ClinVar contains an entry for this variant (Variation ID: 157930). Experimental studies for this missense change are conflicting. A study has shown a defect in copper trafficking, but normal phosphorylation activity in a baculovirus system (PMID: 22240481), while other studies have shown no defect in copper trafficking (PMID: 17919502, 18203200, 24706876). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.