ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2297C>T (p.Thr766Met) (rs121907997)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780926 SCV000918581 likely pathogenic Wilson disease 2020-12-04 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2297C>T (p.Thr766Met) results in a non-conservative amino acid change located in the Transmembrane domain 4 (Dong 2016) 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 3.6e-05 in 250922 control chromosomes. c.2297C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Cox_2005, Mukherjee_2014, Dong_2016, Pham_2017, Shim_2018, Ferenci_2019, Singh_2019). 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 uncertain significance. In addition, p.Thr766Arg has been reported to associate with Wilson Disease. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780926 SCV001414069 uncertain significance Wilson disease 2019-06-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 766 of the ATP7B protein (p.Thr766Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121907997, ExAC 0.006%). This variant has been observed in several individuals affected with Wilson disease, but the presence of a second variant was not established in most cases (PMID: 16088907, 29930488, 24094725, 26483271, 27022412, 29321352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr766 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15557537, 21956287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780926 SCV001474307 likely pathogenic Wilson disease 2020-06-15 criteria provided, single submitter clinical testing The ATP7B c.2297C>T; p.Thr766Met variant (rs121907997) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease (Cox 2005, Dong 2016, Mukherjee 2014). The variant is reported in the ClinVar database (Variation ID: 633064) and is listed in the general population with an overall allele frequency of 0.0039% (11/280,966 alleles) in the Genome Aggregation Database. The threonine at codon 766 is highly conserved, occurs in the highly conserved transmembrane domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.2297C>G; p.Thr766Arg) has been reported in individuals with Wilson disease (Pendlebury 2004, Wilcox 2011). Based on available information, this variant is considered to be likely pathogenic. References: Cox DW et al. Twenty-four Novel Mutations in Wilson Disease Patients of Predominantly European Ancestry. Hum Mutat. 2005 Sep;26(3):280. 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. Mukherjee S et al. Genetic Defects in Indian Wilson Disease Patients and Genotype-Phenotype Correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81 Pendlebury ST et al. Strokelike Presentation of Wilson Disease With Homozygosity for a Novel T766R Mutation. Neurology. 2004 Nov 23;63(10):1982-3. Wilcox RA et al. Whispering Dysphonia in an Australian Family (DYT4): A Clinical and Genetic Reappraisal. Mov Disord. 2011 Nov;26(13):2404-8.

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