Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Soonchunhyang University Bucheon Hospital, |
RCV000004055 | SCV000267218 | uncertain significance | Wilson disease | 2016-03-18 | criteria provided, single submitter | reference population | |
Invitae | RCV000004055 | SCV000626845 | pathogenic | Wilson disease | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 874 of the ATP7B protein (p.Ala874Val). This variant is present in population databases (rs121907994, gnomAD 0.05%). This missense change has been observed in individuals with Wilson disease, with evidence of co-segregation with disease (PMID: 10544227, 10721669, 11775208, 12376745, 12544487, 16998622, 18156766, 21707886, 22735241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3851). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000004055 | SCV000916640 | pathogenic | Wilson disease | 2018-11-16 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.2621C>T (p.Ala874Val) results in a non-conservative amino acid change in the P-type ATPase, A domain superfamily of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246236 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.2621C>T, has been reported in the literature in multiple individuals affected with Wilson Disease in both compound heterozygotes and homozygotes (Lee_2011, Dong_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function evaluating copper transport. The most pronounced variant effect results in 10-30% of normal copper transport rate activity (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic. |
Ce |
RCV001091639 | SCV001247798 | pathogenic | not provided | 2017-08-01 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000004055 | SCV001712292 | pathogenic | Wilson disease | 2021-05-18 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV001091639 | SCV001716163 | pathogenic | not provided | 2021-04-20 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001091639 | SCV001781887 | pathogenic | not provided | 2020-04-09 | criteria provided, single submitter | clinical testing | Published functional studies using the baculovirus expression system in Sf9 cells showed partial transport activity (Huster et al. 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30275481, 31980526, 31743419, 9452121, 30702195, 30655162, 29961769, 11775208, 21707886, 10544227, 12544487, 27398169, 16998622, 22735241, 11043508, 28515472, 16207219, 25704634, 23275100, 22308153, 22484412, 26782526, 19419418, 29381936, 28212618, 26269689, 22692182, 10721669, 22240481, 24253677, 26215059, 25988284, 12376745, 18156766) |
Revvity Omics, |
RCV000004055 | SCV002021406 | pathogenic | Wilson disease | 2020-08-05 | criteria provided, single submitter | clinical testing | |
Provincial Medical Genetics Program of British Columbia, |
RCV000004055 | SCV002496401 | pathogenic | Wilson disease | 2022-01-01 | criteria provided, single submitter | clinical testing | |
Ai |
RCV001091639 | SCV002501994 | likely pathogenic | not provided | 2022-02-16 | criteria provided, single submitter | clinical testing | |
Payam Genetics Center, |
RCV000004055 | SCV003914808 | likely pathogenic | Wilson disease | 2023-03-01 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000004055 | SCV004216314 | pathogenic | Wilson disease | 2023-09-28 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000004055 | SCV000024221 | pathogenic | Wilson disease | 2009-04-01 | no assertion criteria provided | literature only | |
Counsyl | RCV000004055 | SCV000487224 | pathogenic | Wilson disease | 2016-10-28 | no assertion criteria provided | clinical testing | |
Sing |
RCV000004055 | SCV000853123 | likely pathogenic | Wilson disease | 2017-06-07 | no assertion criteria provided | curation | |
Natera, |
RCV000004055 | SCV001459723 | pathogenic | Wilson disease | 2020-09-16 | no assertion criteria provided | clinical testing |