ClinVar Miner

Submissions for variant NM_000053.3(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
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.
Integrated Genetics/Laboratory Corporation of America RCV000586649 SCV000694444 uncertain significance not provided 2016-12-21 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.3316G>A (p.Val1106Ile) variant involves the alteration of a conserved nucleotide and is located in the P-type ATPase, cytoplasmic domain N (InterPro). 2/4 in silico tools predict a damging outcome for this variant. This variant was found in 17/121816 control chromosomes at a frequency of 0.0001396, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant is more common in East Asian subpopulation from ExAC with an allele frequency of 0.17% (15/8626 chromosomes). In literature, this variant has been reported in a large number of WD patients, primarily of Asian (Chinese) origin but without strong evidence for pathogenicity (such as cosegregation with disease). This variant also has been reported to be found in the same allele with other pathogenic variant(s) (Wu_2001, Dong_2016), an evidence against pathogenicity. A small case-control study, however, showed odds ratio (OR) to be 10.444 (95%CI=1.364-79.969), suggesting that this variant may be a risk allele for Wilson disease. More reproducible and large studies are required to confirm this finding. A yeast functional assay showed no significant reduction in ATP7B p.V1106I's ability to restore the Delta-ccc2 mutant strain (Park_2007). Furthermore, confocal images of p.Val1106Ile showed that it was localized to the same trans-Golgi network in COS-7 cells as wild-type ATP7B. Another variant at the same residue V1106D is however functionally deficient (PMID: 18203200). Taken together, there are some conflicts regarding pathogenicity; therefore, this variant is classified as VUS until additional information becomes available.

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