ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3316G>A (p.Val1106Ile) (rs541208827)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586649 SCV000694444 uncertain significance not specified 2019-06-13 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3316G>A (p.Val1106Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 280988 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The frequency within the East Asian subpopulation is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (WD) (0.0017 vs. 0.0054), allowing no conclusion about variant significance. In the literature, this variant has been reported in a large number of WD patients, primarily of Asian (Chinese and Korean) origin, but without strong evidence for pathogenicity (i.e. the presence- and phase of co-occurring variants were not specified in many of these reports, and cosegregation with the disease was not reported). This variant has also been reported to be found in the same allele with other pathogenic variants (Wu_2001, Dong_2016), providing evidence against pathogenicity. However, a small case-control study showed an odds ratio (OR) of ~10.5 (95%CI=1.36-79.9), suggesting that this variant may be a risk allele for Wilson disease (Dong_2016). Larger studies are required to confirm this finding. A functional assay showed no significant reduction in the variant's ability to rescue the delta-ccc2 yeast strain (i.e. the strain lacking the yeast gene ortholog), furthermore, confocal images showed that the variant protein localized to the same trans-Golgi network in COS-7 cells as the wild-type ATP7B (Park_2007). However, another study noted that the activity of Cu-ATPase in lymphocytes from a compound heterozygous patient was decreased by ~45% (Liu_2004). Furthermore, another missense variant affecting the same residue (V1106D) was reported as functionally deficient (PMID: 18203200). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000674801 SCV000800200 likely pathogenic Wilson disease 2018-05-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000674801 SCV000915634 likely pathogenic Wilson disease 2018-10-05 criteria provided, single submitter clinical testing The ATP7B c.3316G>A (p.Val1106Ile) variant is a missense variant that has been widely reported in association with Wilson disease, primarily in individuals of Asian ancestry. Across a selection of the available literature, it was reported in a heterozygous state in at least 25 affected individuals (Wu et al. 2001; Liu et al. 2004; Li et al. 2011; Abuduxikuer et al. 2014; Mukherjee et al. 2014; Tu et al. 2015; Zong and Kong 2015; Dong et al. 2016; Hua et al. 2016; Poon et al. 2016; Yu et al. 2017). The presence and phase of additional variants were not clearly reported in many cases, but at least seven patients were compound heterozygous. In at least one case, the p.Val1106Ile variant was found in cis with a known pathogenic variant. These reports include a small case-control study, which found an OR of 10.44 (95% CI 1.36-79.97, corrected for multiple comparisons) for this variant (Dong et al. 2016). The p.Val1106Ile variant was identified in one out of 663 ethnically matched control individuals and is reported at a frequency of 0.001802 in the East Asian population of the Genome Aggregation Database. Functional studies in COS-7 cells suggested the variant, which is located in the ATP binding domain, does not impair protein localization, and studies in yeast indicated a minor impact on transport function (Park et al. 2007). However, lymphocytes from a compound heterozygous carrier showed ~45% of normal copper ATPase activity (Liu et al. 2004). Based on the collective evidence, the p.Val1106Ile variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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