ClinVar Genomic variation as it relates to human health

Variant summary: ATP7B c.-676A>G is located in the untranscribed region upstream of the ATP7B gene region. The variant allele was found at a frequency of 0.00016 in 31402 control chromosomes (gnomAD). c.-676A>G has been reported in the literature in multiple individuals affected with Wilson Disease (examples: Mukherjee_2014 and Lu_2014). These data indicate that the variant is very likely to be associated with disease. Functional analysis have demonstrated that c.-676A>G reduced promotor activity, however, this report does not allow convincing conclusions about the variant effect in vivo (Mukherjee_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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.

PM3, PS3, PS4_moderate

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 is present in population databases (no rsID available, gnomAD 0.3%). This variant has been observed in individual(s) with Wilson disease (PMID: 24094725, 30087448; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 393099). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATP7B function (PMID: 24094725, 30087448). For these reasons, this variant has been classified as Pathogenic.

Functional analysis in one study found that c.-676 A>G was associated with some reduction in promotor activity, however the significance of this is unclear (PMID: 30087448, 24094725); This variant is associated with the following publications: (PMID: 24094725, 33971252, 30087448, 24878384)

The ATP7B c.-676A>G variant is located in the 5' untranslated region. This variant is also referred to as chr13:g.52,586,149T>C (NC_000013.10, hg19) in the literature. It has been reported in the homozygous state in two individuals with Wilson disease (Chen et al. 2018. PubMed ID: 30087448; Lu et al. 2014. PubMed ID: 24878384, Table 2, Patient WD001). However, one of these individuals harbored multiple additional variants in ATP7B (Lu et al. 2014. PubMed ID: 24878384, Table 2, Patient WD001).  This variant has also been reported in additional individuals with Wilson Disease, however clinical details were not provided  (Lu et al. 2014. PubMed ID: 24878384, Table 2;Mukherjee et al. 2014. PubMed ID: 24094725). Functional assessment using luciferase promoter-reporter assays indicate that this variant leads to a decrease in reporter expression (Mukherjee et al. 2014. PubMed ID: 24094725, Figure 2; Chen et al. 2018. PubMed ID: 30087448, Figure 2). This variant has been reported 5 times among ~31,000 alleles (~0.02%) in a large population database, and is interpreted as uncertain significance, likely pathogenic, and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/393099/). Based on these observations, the c.-676A>G variant is interpreted as likely pathogenic.