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NM_000053.4(ATP7B):c.2305A>G (p.Met769Val)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
12 (Most recent: Nov 19, 2021)
Last evaluated:
Aug 10, 2021
Accession:
VCV000035706.18
Variation ID:
35706
Description:
single nucleotide variant
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NM_000053.4(ATP7B):c.2305A>G (p.Met769Val)

Allele ID
44370
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
13q14.3
Genomic location
13: 51958361 (GRCh38) GRCh38 UCSC
13: 52532497 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P35670:p.Met769Val
NC_000013.10:g.52532497T>C
NC_000013.11:g.51958361T>C
... more HGVS
Protein change
M769V, M685V, M658V
Other names
-
Canonical SPDI
NC_000013.11:51958360:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00007
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Links
ClinGen: CA171300
UniProtKB: P35670#VAR_000725
dbSNP: rs193922103
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 9 criteria provided, multiple submitters, no conflicts Aug 10, 2021 RCV000029355.20
Pathogenic 3 criteria provided, multiple submitters, no conflicts Jul 6, 2021 RCV000078041.8
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
ATP7B - - GRCh38
GRCh37
1325 1389

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
pathogenic
(Aug 18, 2011)
criteria provided, single submitter
Method: curation, clinical testing
Wilson Disease
(autosomal recessive)
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052002.1
Submitted: (Aug 18, 2011)
Evidence details
Publications
PubMed (6)
Comment:
Converted during submission to Pathogenic.
Pathogenic
(Aug 14, 2017)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: germline
Genetic Services Laboratory,University of Chicago
Accession: SCV000192325.2
Submitted: (Apr 04, 2018)
Evidence details
Pathogenic
(Jun 28, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000232468.5
Submitted: (Jun 30, 2017)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Pathogenic
(Oct 30, 2020)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: germline
Invitae
Accession: SCV000626842.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change replaces methionine with valine at codon 769 of the ATP7B protein (p.Met769Val). The methionine residue is highly conserved and there is a … (more)
Pathogenic
(Jul 06, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000520885.5
Submitted: (Sep 28, 2021)
Evidence details
Comment:
Published functional studies found M767V is associated with significantly reduced copper uptake and decreased thermal stability compared to wildtype (Forbes et al., 1998; Huster et … (more)
Pathogenic
(Jan 11, 2019)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157524.1
Submitted: (Aug 05, 2019)
Evidence details
Comment:
The ATP7B c.2305A>G; p.Met769Val variant (rs193922103) is reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with Wilson disease … (more)
Likely pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: germline
Baylor Genetics
Accession: SCV001163734.1
Submitted: (Sep 27, 2019)
Evidence details
Pathogenic
(Dec 24, 2019)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: unknown
Myriad Women's Health, Inc.
Accession: SCV001193881.2
Submitted: (Jun 18, 2020)
Evidence details
Publications
PubMed (7)
Comment:
NM_000053.3(ATP7B):c.2305A>G(M769V) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9837819, 19118915, 23518715, 22692182, 24253677, 22240481 … (more)
Pathogenic
(Feb 17, 2021)
criteria provided, single submitter
Method: clinical testing
Not provided
Allele origin: germline
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716169.1
Submitted: (May 26, 2021)
Evidence details
Publications
PubMed (16)
Comment:
PS4, PS3, PM2, PM5, PP4, PP5
Pathogenic
(Aug 10, 2021)
criteria provided, single submitter
Method: clinical testing
Wilson disease
Allele origin: germline
Nilou-Genome Lab
Accession: SCV001977330.1
Submitted: (Oct 12, 2021)
Evidence details
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Wilson disease
Allele origin: germline
Natera, Inc.
Accession: SCV001463836.1
Submitted: (Dec 28, 2020)
Evidence details
Pathogenic
(Sep 28, 2020)
no assertion criteria provided
Method: clinical testing
Wilson disease
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002024419.1
Submitted: (Nov 19, 2021)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells. Parisi S Scientific reports 2018 PMID: 29674751
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. Reuter MS CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2018 PMID: 29431110
Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. Tuan Pham LA Journal of genetics 2017 PMID: 29321352
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
Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene. Bem RS Arquivos de neuro-psiquiatria 2013 PMID: 23982005
A genetic study of Wilson's disease in the United Kingdom. Coffey AJ Brain : a journal of neurology 2013 PMID: 23518715
Establishment of hepatic and neural differentiation platforms of Wilson's disease specific induced pluripotent stem cells. Yi F Protein & cell 2012 PMID: 22806248
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
Clinical presentation and mutations in Danish patients with Wilson disease. Møller LB European journal of human genetics : EJHG 2011 PMID: 21610751
Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Zhang S Human molecular genetics 2011 PMID: 21593220
Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. Weiss KH Journal of inherited metabolic disease 2010 PMID: 20517649
Genotype-phenotype correlation in Italian children with Wilson's disease. Nicastro E Journal of hepatology 2009 PMID: 19118915
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
Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. de Bie P Journal of medical genetics 2007 PMID: 17717039
Sequence variation database for the Wilson disease copper transporter, ATP7B. Kenney SM Human mutation 2007 PMID: 17680703
Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B). Cater MA The Biochemical journal 2007 PMID: 16939419
Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Gu YH Clinical genetics 2003 PMID: 14986826
Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Huster D Gastroenterology 2003 PMID: 12557139
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 and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Wu ZY Archives of neurology 2001 PMID: 11405812
High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. García-Villarreal L Hepatology (Baltimore, Md.) 2000 PMID: 11093740
Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Forbes JR Human molecular genetics 2000 PMID: 10942420
A study of Wilson disease mutations in Britain. Curtis D Human mutation 1999 PMID: 10502777
Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Forbes JR American journal of human genetics 1998 PMID: 9837819
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
The Wilson disease gene: spectrum of mutations and their consequences. Thomas GR Nature genetics 1995 PMID: 7626145
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B - - - -

Text-mined citations for rs193922103...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 28, 2021