rs764131178
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.3182G>A(p.Gly1061Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 4.98
Genes affected
ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a helix (size 11) in uniprot entity ATP7B_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000053.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 13-51944170-C-T is Pathogenic according to our data. Variant chr13-51944170-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 312383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51944170-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3182G>A | p.Gly1061Glu | missense_variant | 14/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249320Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135342
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727232
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The ATP7B c.3182G>A (p.Gly1061Glu) missense variant has been well-documented as a pathogenic variant for Wilson disease in many different populations. Across a selection of available literature, the p.Gly1061Glu variant has been identified in a homozygous state in seven patients, in a compound heterozygous state in six patients, and in a heterozygous state in four patients in whom a second variant was not identified (Curtis et al. 1999; Loudianos et al. 1999; Margarit et al. 2005; Santhosh et al. 2006; Khan et al. 2012; Guggilla et al. 2015). Gupta et al. (2007) also found the p.Gly1061Glu variant on 11% of Wilson disease patient chromosomes in the Indian population. The p.Gly1061Glu variant was absent from 222 controls and is reported at a frequency of 0.00036 in the South Asian population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Gly1061Glu variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 25, 2024 | This missense variant replaces glycine with glutamic acid at codon 1061 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). This variant occurs in the functionally important ATP nucleotide-binding (N) domain (a.a. 1032 - 1196) that mediates the generation of energy need to transport copper (PMID: 35245129). A functional study showed that the variant resulted in ATP7B retention in the endoplasmic reticulum, inhibition of copper transport, and lower ATP7B protein expression compared to wild-type (PMID: 32778786). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 11216666, 10544227, 15024742, 15523622, 15952988, 17264425, 17634212, 17823867, 19172127, 20517649, 20967755, 23518715, 24094725, 25982861, 27982432, 30120852, 31059521, 34002136, 35535059), including in the homozygous state with no evidence of consanguinity (PMID: 10502777, 15952988, 20517649, 23518715, 31059521) and in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 10544227, 15024742, 15952988, 17823867, 20967755, 23518715, 30120852, 34002136, 35535059). This variant has been identified in 12/249320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 09, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1061 of the ATP7B protein (p.Gly1061Glu). This variant is present in population databases (rs764131178, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 10544227, 15024742, 17264425, 17823867). ClinVar contains an entry for this variant (Variation ID: 312383). 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%. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 07, 2021 | A heterozygous missense variation in exon 14 of the ATP7B gene that results in the amino acid substitution of Glutamic acid for Glycine at codon 1061 was detected. The observed variation c.3182G>A (p.Gly1061Glu) lies in the haloacid dehalogenase-like hydrolase domain of the ATP7B protein and has previously been reported in patients affected with Wilson disease [Roy et al. 2020]. The functional studies showed that this variation causes ATP7B retention in the endoplasmic reticulum, inhibits Cu-transport, and lowers ATP7B protein abundance [Roy et al. 2020]. The variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in silico predictions of the variant is probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 23, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | The p.Gly1061Glu variant has been reported in many individuals with Wilson disease, including at least 3 homozygotes and 7 compound heterozygotes (Curtis 1999, Guggilla 2015, Gupta 2007, Loudianos 1999, Margarit 2005, Santhosh 2006). This variant was identified in 0.03% (12/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough frequency to be consistent with a recessive allele. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000312383, PMID:10502777). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 10544227). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:30655162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.928>=0.6, 3CNET: 0.933>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000481). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 22, 2023 | The observed missense c.3182G>Ap.Gly1061Glu variant in ATP7B gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Wilson disease Tasmeen et al., 2022. The functional studies showed that this variation causes ATP7B retention in the endoplasmic reticulum, inhibits Cu-transport, and lowers ATP7B protein abundance Roy et al., 2020. This variant is reported with the allele frequency of 0.005% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid Gly at position 1061 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly1061Glu in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 24, 2021 | PS4, PS3, PM1, PM2, PP3, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 16, 2021 | Found on 11% of Wilson disease patient chromosomes in the Indian population (Gupta et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10502777, 22692182, 25982861, 33083013, 31589614, 24094725, 23430908, 18371106, 26207595, 17634212, 25900946, 17823867, 17264425, 15952988, 30120852, 15024742, 10544227) - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 12, 2017 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2017 | The p.G1061E pathogenic mutation (also known as c.3182G>A), located in coding exon 14 of the ATP7B gene, results from a G to A substitution at nucleotide position 3182. The glycine at codon 1061 is replaced by glutamic acid, an amino acid with similar properties. This mutation is one of three common mutations often found in individuals with Wilson disease from South and East India, but has also been reported in affected individuals from other regions (Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Guggilla SR et al. Gene, 2015 Sep;569:83-7). This mutation has been identified in multiple homozygous and compound heterozygous individuals with Wilson disease (Curtis D et al. Hum. Mutat., 1999;14:304-11; Margarit E et al. Clin. Genet., 2005 Jul;68:61-8; Santhosh S et al. Indian J Gastroenterol, 2006;25:277-82; Gupta A et al. Cell. Mol. Neurobiol., 2007 Dec;27:1023-33; Mukherjee S et al. Parkinsonism Relat. Disord., 2014 Jan;20:75-81; Guggilla SR et al. Gene, 2015 Sep;569:83-7). Another study, in which authors modeled the structural effects of various mutations on the ATP7B gene, showed that this mutation site is sensitive to substitutions (Schushan M et al. Metallomics, 2012 Jul;4:669-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;T
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;B;D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at