13-51939062-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM5PP5BS2_Supporting
The NM_000053.4(ATP7B):āc.3688A>Gā(p.Ile1230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,614,256 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1230T) has been classified as Likely pathogenic.
Frequency
Genomes: š 0.00049 ( 0 hom., cov: 33)
Exomes š: 0.00068 ( 2 hom. )
Consequence
ATP7B
NM_000053.4 missense
NM_000053.4 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 7.97
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 Uncertain_significance. Variant got 2 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-51939061-A-G is described in Lovd as [Likely_pathogenic].
PP5
Variant 13-51939062-T-C is Pathogenic according to our data. Variant chr13-51939062-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312379.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=11, Pathogenic=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3688A>G | p.Ile1230Val | missense_variant | 17/21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP7B | ENST00000242839.10 | c.3688A>G | p.Ile1230Val | missense_variant | 17/21 | 1 | NM_000053.4 | ENSP00000242839 | P1 |
Frequencies
GnomAD3 genomes 0.000486 AC: 74AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000321 AC: 80AN: 249584Hom.: 0 AF XY: 0.000362 AC XY: 49AN XY: 135410
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GnomAD4 exome AF: 0.000675 AC: 987AN: 1461890Hom.: 2 Cov.: 32 AF XY: 0.000671 AC XY: 488AN XY: 727248
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GnomAD4 genome 0.000486 AC: 74AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38AN XY: 74512
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wilson disease Pathogenic:7Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 19, 2023 | This ATP7B missense variant has been reported in individuals with clinical features of Wilson disease, and at least one of these individuals had a second variant in trans that was established to be pathogenic. This variant (rs200911496) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 74/152248 total alleles; 0.05%; no homozygotes). It has been reported in ClinVar (Variation ID 312379). Two bioinformatic tools queried predict that this substitution would be damaging, and the isoleucine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.3688A>G; p.Ile1230Val in ATP7B to be uncertain at this time. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 27, 2023 | The ATP7B c.3688A>G; p.Ile1230Val variant (rs200911496) is reported in the literature in individuals affected with Wilson disease (Davies 2008, Denoyer 2013, Otto 2016), including in the compound heterozygous state with another pathogenic variant (Denoyer 2013). This variant is reported in ClinVar (Variation ID: 312379), and found in the general population with an overall allele frequency of 0.034% (96/280998 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.801). Additionally, another variant at this codon (c.3689T>C; p.Ile1230Thr) has been reported in the compound heterozygous state in an individual with Wilson disease (Li 2019). Based on available information, the p.Ile1230Val variant is considered likely pathogenic. References: Davies LP et al. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008 Mar;12(1):139-45. PMID: 18373411. Denoyer Y et al. Neurological Wilson's disease lethal for the son, asymptomatic in the father. Mov Disord. 2013 Mar;28(3):402-3. PMID: 23389864. Li X et al. Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. Hum Mutat. 2019 May;40(5):552-565. PMID: 30702195. Otto PA et al. Estimation of Allele Frequencies and Population Incidence of Wilson Disease in Brazil. Prensa Med Argent 2016, 102:5. http://dx.doi.org/10.4172/lpma.1000228 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.3688A>G (p.Ile1230Val) variant has been reported in association with Wilson disease at least two patients in a compound heterozygous state (Davies et al. 2008; Denoyer et al. 2012). One patient was described as being asymptomatic, but showed slightly altered copper metabolism upon further serological and urine testing (Denoyer et al. 2012). This variant was absent from 53 control chromosomes from European individuals and is suggested to be in a well-conserved region (Davies et al. 2008). The p.Ile1230Val variant is reported at a frequency of 0.0005 in the European (Non-Finnish) population of the Exome Aggregation Consortium, including in one individual in a homozygous state. The evidence for this variant is limited. The p.Ile1230Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 10, 2022 | This missense variant replaces isoleucine with valine at codon 1230 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 reported in individuals affected with Wilson disease (PMID: 18373411, 23389864; DOI:10.4172/lpma.1000228), intellectual disability (PMID: 28554332), and schizophrenia (PMID: 30556376). This variant has been identified in 96/280998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Likely pathogenic, criteria provided, single submitter | research | Institute of Genomics, University of Tartu | Apr 04, 2023 | This ATP7B c.3688A>G; p.Ile1230Val variant (rs200911496) was identified in the 2020-2023 Wilson's disease genotype-first recall study at the Estonian Biobank. We classified this variant as likely pathogenic according to Richards et al. 2015 ACMG guidelines. Evidence: PM2 (recessive disease, GnomAD global AF 0.0006), PM3 (found in trans with another pathogenic variant (p.H1069Q) in our recall study, previously also described in PMID: 23389864), PP3 (CADD 24.9, METALR 0.87 D, MutationTester D), PP4 (PMID: 18373411, 23389864, also see clinical features) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 10, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wilson disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (96 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated hydrolase domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to threonine at the same residue has previously been reported as pathogenic in a patient with Wilson disease. The variant was compound heterozygous and functional studies demonstrated a significant reduction in cell growth (PMID: 30702195). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported as both pathogenic and a VUS, in patients with Wilson disease and in unaffected carriers (ClinVar, HGMD, LOVD, PMID: 18373411, PMID: 23389864, PMID: 30097039, PMID: 30556376). (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1230 of the ATP7B protein (p.Ile1230Val). This variant is present in population databases (rs200911496, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of Wilson disease (PMID: 18373411, 23389864). 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: 312379). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. This variant disrupts the p.Ile1230 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30702195; Invitae). 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 | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces isoleucine with valine at codon 1230 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 reported in individuals affected with Wilson disease (PMID: 18373411, 23389864; DOI:10.4172/lpma.1000228), intellectual disability (PMID: 28554332), and schizophrenia (PMID: 30556376). This variant has been identified in 96/280998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 25, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2024 | Identified in a patient with Wilson disease; however, detailed clinical information was not provided (PMID: 18373411); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20465995, 22692182, 32248359, 34426522, 30556376, 30275481, 26752957, 31059521, 28554332, 28050010, 26986070, 30702195, 30019023, 26659599, 30097039, 29790872, 28440294, 23389864, 33972609, 18373411, 36890159) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | ATP7B: PM3, PM5, PM2:Supporting - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: p.Ile1230Val in HGMD. Reported in one publication in patient(s) with Wilson disease (Davies 2008; full text not available). 0.1% in ExAC, including 1 homozygote. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 26, 2022 | Variant summary: ATP7B c.3688A>G (p.Ile1230Val) results in a conservative amino acid change located in the ATP loop of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251268 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00032 vs 0.0054), allowing no conclusion about variant significance. c.3688A>G has been reported in the literature as a non-informative genotype (complete genotype not specified) in individuals affected with Wilson Disease (example, Davies_2008, Otto_2016, Sriretnakumar_2018) and one as a secondary carrier genotype in an individual with developmental and/or intellectual delays (example, Bowling_2017). Denoyer_2013 reports the variant to occur in a family in which the proband diagnosed with Wilson Disease was a compound heterozygote for two different variants, namely p.Glu127LysfsX26/p.Gly691Arg and his father who was indicated to be clinically asymptomatic although presenting with a right Kayser-Fleischer ring and altered copper levels was a compound heterozygote for this variant (p.Ile1230Val) and p.Gly691Arg. These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=4; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
ATP7B-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2024 | The ATP7B c.3688A>G variant is predicted to result in the amino acid substitution p.Ile1230Val. This variant has been reported in patients with Wilson disease in the compound heterozygous state (Davies et al. 2008. PubMed ID: 18373411). Some reports indicate that it may cause a mild or asymptomatic form of the disease (Denoyer et al. 2013. PubMed ID: 23389864; Wallace and Dooley. 2020. PubMed ID: 32248359). This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD. A different missense change affecting this amino acid has been reported in the compound heterozygous state in a patient and has been shown to impact protein function (c.3689T>C, p.Ile1230Thr; Li et al. 2019. PubMed ID: 30702195). We interpret the c.3688A>G variant as likely pathogenic. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 14, 2021 | Davies, 2008; Denoyer, 2013 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N
REVEL
Pathogenic
Sift
Benign
T;D;D;T;T;.;D
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
D;P;D;P;D;D;D
Vest4
MVP
MPC
ClinPred
T
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gMVP
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at