Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000674801 | SCV000694444 | likely pathogenic | Wilson disease | 2022-08-22 | 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, some patients are compound heterozygotes. 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, other missense variants affecting the same residue (p.V1106D, p.V1106L) have been reported to associate with Wilson disease and p.V1106D was reported as functionally deficient (PMID: 18203200). Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. One ClinVar submission cites the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Counsyl | RCV000674801 | SCV000800200 | likely pathogenic | Wilson disease | 2018-05-25 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
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. |
| Invitae | RCV000674801 | SCV001411757 | pathogenic | Wilson disease | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1106 of the ATP7B protein (p.Val1106Ile). This variant is present in population databases (rs541208827, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 14966923, 26483271, 28212618, 30702195). ClinVar contains an entry for this variant (Variation ID: 495414). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Genome- |
RCV000674801 | SCV001977133 | likely pathogenic | Wilson disease | 2021-08-10 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV002261126 | SCV002541578 | uncertain significance | not provided | 2022-12-22 | criteria provided, single submitter | clinical testing | BS3, PP4, PM2, PM3, PM5, PS4_moderate |
| ARUP Laboratories, |
RCV000674801 | SCV003799834 | uncertain significance | Wilson disease | 2022-04-01 | criteria provided, single submitter | clinical testing | The ATP7B c.3316G>A; p.Val1106Ile variant (rs541208827) is reported in the literature in several individuals affected with Wilson disease (Mukherjee 2014, Qian 2019, Xiao 2021, Yu 2017). However, a second pathogenic variant was only reported in a minority of cases (Liu 2004, Qian 2019, Yu 2017). In addition, a small case-control study showed an odds ratio (OR) in favor of pathogenicity of ~10.5 (95%CI=1.36-79.9, Dong 2016). Functional analyses of the variant protein show no change from wild type in the variant's ability to rescue the delta-ccc2 yeast strain, and the variant protein localized to the same trans-Golgi network in COS-7 cells as wild-type ATP7B (Park 2007). However, lymphocytes from a compound heterozygous carrier showed ~45% of normal copper ATPase activity (Liu 2004). This variant is reported in ClinVar (Variation ID: 495414) and is found in the East Asian population with an allele frequency of 0.17% (33/19538 alleles) in the Genome Aggregation Database. The valine at codon 1106 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.619). Due to conflicting information, the clinical significance of the p.Val1106Ile variant is uncertain at this time. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Liu XQ et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol. 2004 Feb 15;10(4):590-3. PMID: 14966923. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. PMID: 24094725. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13. PMID: 17587212. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649. PMID: 30884209. Xiao Z et al. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med. 2021 Sep;9(9):e1735. PMID: 34324271. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. PMID: 28212618. |
| Baylor Genetics | RCV000674801 | SCV004216268 | likely pathogenic | Wilson disease | 2023-10-26 | criteria provided, single submitter | clinical testing |