Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000169237 | SCV000220509 | pathogenic | Wilson disease | 2014-07-13 | criteria provided, single submitter | literature only | |
Eurofins Ntd Llc |
RCV000723473 | SCV000224751 | pathogenic | not provided | 2014-07-07 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000723473 | SCV000602597 | pathogenic | not provided | 2018-03-20 | criteria provided, single submitter | clinical testing | The ATP7B c.2532delA, p.Val845fs variant (rs755709270) has been reported in multiple patients diagnosed with Wilson's disease (Abdelghaffar 2008, Abdel Ghaffar 2011, Figus 1995, Gromadzka 2005, Lepori 2012, Panagiotakaki 2004, Simsek Papur 2013). The variant is reported in the ClinVar database (Variation ID: 188883). The variant is listed in the Genome Aggregation Database in 2 out of 277206 alleles, indicating it is not a common polymorphism. The variant deletes one nucleotide, causes a frameshift, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, the variant is classified as pathogenic. References: Abdelghaffar T et al. Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet. 2008; 53(8):681-7. Abdel Ghaffar T et al. Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. BMC Pediatr. 2011; 11:56. Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995; 57(6):1318-24. Gromadzka G et al. Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease. Clin Genet. 2005; 68(6):524-32. Lepori M et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 26(4):147-50. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004; 131(2):168-73. |
Invitae | RCV000169237 | SCV000817268 | pathogenic | Wilson disease | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Val845Serfs*28) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs755709270, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 8533760, 11243728, 15523622, 24517292). This variant is also known as K844K-fs. ClinVar contains an entry for this variant (Variation ID: 188883). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169237 | SCV000918582 | pathogenic | Wilson disease | 2018-02-16 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.2532delA (p.Val845SerfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2832delT (p.Phe944fsX23), c.3402delC (p.Ala1135fsX13), c.3955C>T (p.Arg1319X)). The variant allele was found at a frequency of 7.2e-06 in 277206 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (7.2e-06 vs 0.0054). The variant c.2532delA has been reported in the literature in several individuals affected with Wilson Disease, either in homozygosity or in compound heterozygosity with other pathogenic ATP7B variants in trans, and many of these patients had also a hepatic presentation (Ferenci 2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Gene |
RCV000723473 | SCV001780512 | pathogenic | not provided | 2023-01-06 | criteria provided, single submitter | clinical testing | Reported as a common pathogenic variant (Figus et al., 1995; Panagiotakaki et al., 2004; Paradisi et al., 2015); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11243728, 24517292, 34400371, 16283883, 30230192, 8533760, 15523622, 25497208, 31589614) |
Genome- |
RCV000169237 | SCV001977313 | pathogenic | Wilson disease | 2021-08-10 | criteria provided, single submitter | clinical testing | |
Johns Hopkins Genomics, |
RCV000169237 | SCV002570363 | pathogenic | Wilson disease | 2022-09-07 | criteria provided, single submitter | clinical testing | This ATP7B frameshift variant (rs755709270) has been reported in the literature in association with Wilson disease. It is rare (<0.1%) in a large population dataset (gnomAD: 2/280944 total alleles; MAF 0.0007119%; no homozygotes) and has an entry in ClinVar (Variation ID 188883). This frameshift variant results in a premature stop codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. |
Victorian Clinical Genetics Services, |
RCV000169237 | SCV002768141 | pathogenic | Wilson disease | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wilson disease (MIM#277900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. At least five individuals have been reported with this variant and is consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Baylor Genetics | RCV000169237 | SCV004216315 | pathogenic | Wilson disease | 2023-09-28 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000169237 | SCV002087844 | pathogenic | Wilson disease | 2020-12-14 | no assertion criteria provided | clinical testing |