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

gnomAD frequency: 0.00001  dbSNP: rs121907997

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780926	SCV001414069	pathogenic	Wilson disease	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 766 of the ATP7B protein (p.Thr766Met). This variant is present in population databases (rs121907997, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 16088907, 24094725, 26483271, 27022412, 29321352, 29930488, 31059521, 33763395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 633064). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. 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. For these reasons, this variant has been classified as Pathogenic.
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.
Genome-Nilou Lab	RCV000780926	SCV001977163	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223938	SCV002502655	likely pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000780926	SCV002809727	likely pathogenic	Wilson disease	2022-04-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002223938	SCV004010246	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Strong, PM2, PM5, PP3, PP4
Baylor Genetics	RCV000780926	SCV004216304	likely pathogenic	Wilson disease	2024-03-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000780926	SCV004845549	likely pathogenic	Wilson disease	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 766 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with autosomal recessive Wilson disease, including in the compound heterozygous and homozygous states (PMID: 16088907, 24094725, 26483271, 27022412, 29321352, 29930488, 30232804, 31059521, 33763395, 34240825). A different variant affecting the same codon, c.2297C>G (p.Thr766Arg), is considered to be disease-causing (ClinVar variation ID: 3861), suggesting that Thr at this position is important for the protein function. This variant has been identified in 11/280966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.