ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.-676A>G (rs1021025464)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426325 SCV000536461 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing The c.-676 A>G has previously been reported in association with Wilson disease in several unrelated individuals with Wilson disease who harbored a second variant in the ATP7B gene (Lu et al., 2014; Mukherjee et al., 2014). Transfection of c.-676 A>G in HEK293 cells found that it was associated with significantly decreased promotor activity compared to wild-type, however, a common benign variant, c.-460 G>A was also found to be associated with an even greater decrease in promotor activity in the same study (Mukherjee et al., 2014). Additionally, although c.-676 A>G was not detected in 100 control chromosomes in one study, data from control individuals in publicly available databases is not available to assess the frequency of c.-676 A>Gin the general population (Mukherjee et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Gill Bejerano Lab,Stanford University RCV000626321 SCV000732048 likely pathogenic Wilson disease 2018-03-27 criteria provided, single submitter research The variant chr13:g.52,586,149T>C (NC_000013.9), is positioned 676 bases upstream of the annotated canonical translation start site of ATP7B, in the proximal promoter. It was verified by Sanger sequencing to be heterozygous in both healthy parents and homozygous in the patient. It has also been observed as heterozygous in 5 East Asian individuals in the Genome Aggregation Database (Lek 2016). The variant chr13:g.52,586,149T>C has previously been observed in heterozygosity in one Chinese (Lu 2014) and ten Indian individuals with Wilson Disease (Mukherjee 2014). In these instances, chr13:g.52,586,149T>C was almost always identified in conjunction with one or more heterozygous ATP7B missense variants (with exceptions where no ATP7B coding variants were detected and yet only this promoter SNV was observed as heterozygous). In vitro studies indicate that chr13:g.52,586,149T>C reduces ATP7B promoter activity, likely through disruption of a metal regulatory transcription factor 1 (MTF1) binding site.
Invitae RCV000626321 SCV000952513 likely pathogenic Wilson disease 2019-01-04 criteria provided, single submitter clinical testing This variant occurs in a non-coding region of the ATP7B gene. It does not change the encoded amino acid sequence of the ATP7B protein. This variant has been observed in individuals with Wilson disease (PMID: 24094725, Invitae). 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: 393099). This variant has been reported to have conflicting or insufficient data to determine the effect on ATP7B protein function (PMID: 24094725). 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.

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