ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.1847G>A (p.Arg616Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000053.4(ATP7B):c.1847G>A (p.Arg616Gln)
Variation ID: 552606 Accession: VCV000552606.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51964894 (GRCh38) [ NCBI UCSC ] 13: 52539030 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 5, 2018 Oct 8, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.1847G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Arg616Gln missense NM_001005918.3:c.1847G>A NP_001005918.1:p.Arg616Gln missense NM_001243182.2:c.1514G>A NP_001230111.1:p.Arg505Gln missense NM_001330578.2:c.1847G>A NP_001317507.1:p.Arg616Gln missense NM_001330579.2:c.1847G>A NP_001317508.1:p.Arg616Gln missense NC_000013.11:g.51964894C>T NC_000013.10:g.52539030C>T NG_008806.1:g.51601G>A - Protein change
- R616Q, R505Q
- Other names
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- Canonical SPDI
- NC_000013.11:51964893:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ATP7B | - | - |
GRCh38 GRCh37 |
2901 | 3044 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000667901.22 | |
Pathogenic (3) |
criteria provided, single submitter
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Apr 1, 2024 | RCV001531802.22 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918593.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of the encoded protein sequence. Four of … (more)
Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246238 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.9e-05 vs 0.0054), allowing no conclusion about variant significance. c.1847G>A has been reported in the literature in multiple individuals affected with Wilson Disease as both a compound heterozygous and homozygous allele (Loudianos_2003, Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368970.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3.
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822112.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with glutamine at codon 616 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glutamine at codon 616 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 10502777, 12885331, 16283883, 17264425, 18286826, 18034201, 21610751, 22735241, 23518715, 23789284, 26799313). In many of these affected individuals, this variant has been determined to be homozygous or compound heterozygous with another pathogenic variant in the same gene (PMID: 12885331, 17264425, 21610751, 22735241, 23518715, 26799313). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 12/249570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg616Trp, is classified as pathogenic (Clinvar Variation ID: 863093), indicating that arginine at this position is important for ATP7b protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 5
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933962.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ATP7B protein (p.Arg616Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ATP7B protein (p.Arg616Gln). This variant is present in population databases (rs752850609, gnomAD 0.009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 12885331, 21610751, 22735241, 26799313). ClinVar contains an entry for this variant (Variation ID: 552606). 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. (less)
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001977361.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Wilson disease
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005052022.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785645.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747089.19
First in ClinVar: Jul 10, 2021 Last updated: Oct 08, 2024 |
Comment:
ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004216308.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jun 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000792424.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930734.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954808.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jul 14, 2020)
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no assertion criteria provided
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002087861.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Wilson disease
Affected status: yes
Allele origin:
unknown
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Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV004024150.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023
Comment:
Compound Heterozygous
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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ATP7B Gene Mutations in Croatian Patients with Wilson Disease. | Ljubić H | Genetic testing and molecular biomarkers | 2016 | PMID: 26799313 |
Mutational analysis of ATP7B gene and the genotype-phenotype correlation in patients with Wilson's disease in Serbia. | Tomić A | Vojnosanitetski pregled | 2013 | PMID: 23789284 |
A genetic study of Wilson's disease in the United Kingdom. | Coffey AJ | Brain : a journal of neurology | 2013 | PMID: 23518715 |
Neurological symptoms, genotype-phenotype correlations and ethnic-specific differences in Bulgarian patients with Wilson disease. | Mihaylova V | The neurologist | 2012 | PMID: 22735241 |
Clinical presentation and mutations in Danish patients with Wilson disease. | Møller LB | European journal of human genetics : EJHG | 2011 | PMID: 21610751 |
Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. | Weiss KH | Journal of inherited metabolic disease | 2010 | PMID: 20517649 |
Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease. | Gojová L | Clinical genetics | 2008 | PMID: 18371106 |
Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. | Mak CM | Journal of human genetics | 2008 | PMID: 18034201 |
Ethnic specific background of mutations in Bulgarian patients with Wilson disease. | Todorov T | Genetic counseling (Geneva, Switzerland) | 2007 | PMID: 18286826 |
Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. | de Bie P | Gastroenterology | 2007 | PMID: 17919502 |
ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients. | Santhosh S | Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology | 2006 | PMID: 17264425 |
Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease. | Gromadzka G | Clinical genetics | 2005 | PMID: 16283883 |
Characterization of the molecular defect in the ATP7B gene in Wilson disease patients from Yugoslavia. | Loudianos G | Genetic testing | 2003 | PMID: 12885331 |
A study of Wilson disease mutations in Britain. | Curtis D | Human mutation | 1999 | PMID: 10502777 |
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Text-mined citations for rs752850609 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.