rs121907997
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.2297C>T(p.Thr766Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T766R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2297C>T | p.Thr766Met | missense_variant | 8/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.2297C>T | p.Thr766Met | missense_variant | 8/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249558Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135396
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727240
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 15, 2020 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 28, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | ATP7B: PM3:Strong, PM2, PM5, PP3, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at