ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.2128G>A (p.Gly710Ser)
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.2128G>A (p.Gly710Ser)
Variation ID: 156281 Accession: VCV000156281.57
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51958538 (GRCh38) [ NCBI UCSC ] 13: 52532674 (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 Oct 6, 2014 Aug 4, 2024 Mar 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.2128G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Gly710Ser missense NM_001005918.3:c.1870-931G>A intron variant NM_001243182.2:c.1795G>A NP_001230111.1:p.Gly599Ser missense NM_001330578.2:c.2122-931G>A intron variant NM_001330579.2:c.1876G>A NP_001317508.1:p.Gly626Ser missense NC_000013.11:g.51958538C>T NC_000013.10:g.52532674C>T NG_008806.1:g.57957G>A P35670:p.Gly710Ser - Protein change
- G710S, G599S, G626S
- Other names
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- Canonical SPDI
- NC_000013.11:51958537: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), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
2894 | 3036 |
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
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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 (10) |
criteria provided, multiple submitters, no conflicts
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Mar 18, 2024 | RCV000144365.36 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000497757.28 |
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
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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
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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
(Dec 20, 2013)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000192320.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(May 21, 2018)
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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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GeneDx
Accession: SCV000589555.2
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The G710S variant in the ATP7B gene has been reported previously in the homozygous and compound heterozygous states in patients with Wilson disease (Waldenstrom et … (more)
The G710S variant in the ATP7B gene has been reported previously in the homozygous and compound heterozygous states in patients with Wilson disease (Waldenstrom et al., 1996; Battisti et al., 1999; Hua et al., 2016). The G710S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G710S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of the G710S variant indicate that this variant leads to significantly decreased copper intake (Huster et al., 2012). Missense variants at the same residue (G710A, G710V) have been reported in individuals with Wilson disease (Ha-Hao et al., 1998; Cox et al., 2005) We interpret G710S as a pathogenic variant. (less)
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Pathogenic
(Dec 18, 2023)
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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: SCV004818658.1
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 glycine with serine at codon 710 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glycine with serine at codon 710 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). Functional studies have shown that this variant disrupts copper transport activity (PMID: 9311736, 22240481, 24253677). This variant has been reported in over thirty individuals affected with Wilson disease (PMID: 8938442, 9311736, 10406672, 10544227, 11690702, 11857545, 15967699, 16133174, 16233999, 17433323, 19596473, 26215059, 27398169). In a number of these individuals, this variant was confirmed to be in the compound heterozygous or homozygous state (PMID: 10406672, 11857545, 16233999, 19596473). This variant has been identified in 4/248838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 15
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Pathogenic
(Mar 18, 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: SCV004216306.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Apr 01, 2023)
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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: SCV001248427.20
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Comment:
ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 23, 2016)
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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: SCV000694414.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The c.2128G>A (p.Gly710Ser) in ATP7B gene is a missense change that is located in a loop 2-3 of the A-domain; it involves a … (more)
Variant summary: The c.2128G>A (p.Gly710Ser) in ATP7B gene is a missense change that is located in a loop 2-3 of the A-domain; it involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. These predictions were confirmed by results of functional studies. The variant is absent from the control population dataset of ExAC. The variant was identified in multiple affected individuals (homozygotes or compound heterozygotes) presented with a classic symptoms of a WD (lowered plasma ceruloplasmin, free serum and urinary copper concentration, and the occurrence of KayserFleischer ringscharacteristic copper deposition in the corneal periphery). The variant of interest has been reported as Pathogenic by reputable database/clinical laboratory. Taking together, the variant was classified as Pathogenic. (less)
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Pathogenic
(Oct 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000702263.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(May 06, 2019)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159106.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The ATP7B c.2128G>A; p.Gly710Ser variant (rs137853285) has been reported in multiple individuals with Wilson disease, either homozygously or compound heterozygously (Hofer 2012, Hua 2016, Li … (more)
The ATP7B c.2128G>A; p.Gly710Ser variant (rs137853285) has been reported in multiple individuals with Wilson disease, either homozygously or compound heterozygously (Hofer 2012, Hua 2016, Li 2011, Shah 1997, Waldenstrom 1996). Additionally, functional analysis has shown the variant protein to have decreased copper uptake and transport (Huster 2012). This variant is reported in ClinVar (Variation ID: 156281), and observed in the general population with a low overall frequency of 0.002% (4/248838 alleles) in the Genome Aggregation Database. The glycine at codon 710 is highly conserved, and computational algorithms (SIFT, PolyPhen-2) predict this variant to be damaging to the protein. Based on the above information, this variant is considered pathogenic. REFERENCES Hofer H et al. Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study. J Hum Genet. 2012 Sep;57(9):564-7. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Li XH et al. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. BMC Med Genet. 2011 Jan 11;12:6. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. (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: SCV001977350.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(May 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716174.2
First in ClinVar: Jun 15, 2021 Last updated: Apr 09, 2023 |
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Pathogenic
(Jan 30, 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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Invitae
Accession: SCV000626836.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 710 of the ATP7B protein (p.Gly710Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 710 of the ATP7B protein (p.Gly710Ser). This variant is present in population databases (rs137853285, gnomAD 0.004%). This missense change has been observed in individual(s) with Wilson disease (PMID: 8938442, 10544227, 15967699, 16133174, 16233999, 17433323, 27398169). ClinVar contains an entry for this variant (Variation ID: 156281). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 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: SCV001463839.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Nov 30, 2016)
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no assertion criteria provided
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132341.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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not provided
(-)
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no classification provided
Method: not provided
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Wilson's disease
Affected status: not provided
Allele origin:
not provided
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000189432.1
First in ClinVar: Oct 06, 2014 Last updated: Oct 06, 2014 |
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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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The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. | Balashova MS | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2020 | PMID: 31708252 |
Mutational analysis of ATP7B in Chinese Wilson disease patients. | Hua R | American journal of translational research | 2016 | PMID: 27398169 |
Clinical and genetic analysis of pediatric patients with Wilson disease. | Şimşek Papur Ö | The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology | 2015 | PMID: 26215059 |
In silico investigation of the ATP7B gene: insights from functional prediction of non-synonymous substitution to protein structure. | Squitti R | Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine | 2014 | PMID: 24253677 |
Mutation analysis of ATP7B gene in Turkish Wilson disease patients: identification of five novel mutations. | Simsek Papur O | European journal of medical genetics | 2013 | PMID: 23333878 |
A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. | Schushan M | Metallomics : integrated biometal science | 2012 | PMID: 22692182 |
Diverse functional properties of Wilson disease ATP7B variants. | Huster D | Gastroenterology | 2012 | PMID: 22240481 |
Hepatocyte GP73 expression in Wilson disease. | Wright LM | Journal of hepatology | 2009 | PMID: 19596473 |
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 |
Late-onset Wilson's disease. | Ferenci P | Gastroenterology | 2007 | PMID: 17433323 |
Wilson's Disease. | Ferenci P | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2005 | PMID: 16233999 |
Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype-phenotype correlation in Indian patients. | Gupta A | Human genetics | 2005 | PMID: 16133174 |
Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. | Vrabelova S | Molecular genetics and metabolism | 2005 | PMID: 15967699 |
Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. | Huster D | Gastroenterology | 2003 | PMID: 12557139 |
Common mutations of ATP7B in Wilson disease patients from Hungary. | Firneisz G | American journal of medical genetics | 2002 | PMID: 11857545 |
High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. | Caca K | Journal of hepatology | 2001 | PMID: 11690702 |
Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. | Loudianos G | Journal of medical genetics | 1999 | PMID: 10544227 |
Detection of a rare Wilson disease mutation associated with arylsulfatase A pseudodeficiency. | Battisti C | American journal of medical genetics | 1999 | PMID: 10406672 |
His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. | Duc HH | European journal of human genetics : EJHG | 1998 | PMID: 9887381 |
Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. | Shah AB | American journal of human genetics | 1997 | PMID: 9311736 |
Efficient detection of mutations in Wilson disease by manifold sequencing. | Waldenström E | Genomics | 1996 | PMID: 8938442 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B | - | - | - | - |
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Text-mined citations for rs137853285 ...
HelpRecord last updated Aug 04, 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.