ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His)
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.
Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000053.4(ATP7B):c.3452G>A (p.Arg1151His)
Variation ID: 495415 Accession: VCV000495415.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51941185 (GRCh38) [ NCBI UCSC ] 13: 52515321 (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 Mar 17, 2018 Apr 20, 2024 Aug 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3452G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Arg1151His missense NM_001005918.3:c.2831G>A NP_001005918.1:p.Arg944His missense NM_001243182.2:c.3119G>A NP_001230111.1:p.Arg1040His missense NM_001330578.2:c.3218G>A NP_001317507.1:p.Arg1073His missense NM_001330579.2:c.3200G>A NP_001317508.1:p.Arg1067His missense NC_000013.11:g.51941185C>T NC_000013.10:g.52515321C>T NG_008806.1:g.75310G>A - Protein change
- R1151H, R944H, R1040H, R1073H, R1067H
- Other names
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- Canonical SPDI
- NC_000013.11:51941184: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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 30, 2016 | RCV000586771.1 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 13, 2023 | RCV000666672.12 |
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
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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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Uncertain significance
(Aug 30, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694447.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The ATP7B c.3452G>A (p.Arg1151His) variant involves the alteration of a conserved nucleotide and this variant is located in the P-type ATPase and/or cytoplasmic … (more)
Variant summary: The ATP7B c.3452G>A (p.Arg1151His) variant involves the alteration of a conserved nucleotide and this variant is located in the P-type ATPase and/or cytoplasmic domain N which is critical for ATP binding. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120874 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been reported in at least 3 WD patients (Loudianos_1999, Li_2011, Dong_2016), one was mentioned to be compound heterozygotes of this variant and Gly1089Glu. One internal sample carries this variant and a pathogenic variant (p.His1069Gln); clinical status as well as phase of the variants unknown. One in vitro study showed that this variant mildly affects the structure and ATP-binding activity of ATP7B protein using N-domain fragment (Morgan_2004). In addition, one reputable database classified this variant as disease variant. Taken together, this variant is classified as VUS-possibly pathogenic. (less)
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Likely pathogenic
(Aug 13, 2023)
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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: SCV004216359.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Feb 11, 2023)
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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: SCV002292010.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. Experimental studies have shown that this missense change affects ATP7B function (PMID: 15205462). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17949296, 21645214, 23333878, 27398169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1151 of the ATP7B protein (p.Arg1151His). This variant is present in population databases (rs377297166, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 30655162). ClinVar contains an entry for this variant (Variation ID: 495415). (less)
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Uncertain Significance
(May 16, 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: SCV004829545.1
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, c.3452G>A, replaces arginine with histidine at codon 1151 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant, c.3452G>A, replaces arginine with histidine at codon 1151 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 showed that this variant has a 1.3 fold reduced affinity to ATP compared with wild-type (PMID: 15205462). This variant has been reported in many individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 21219664, 27022412, 27398169, 27982432). In one affected individual, this variant was observed in the compound heterozygous state with a second pathogenic variant (PMID: 10544227), indicating that this variant contributes to disease. Additionally, in three affected individuals, a second co-occurring pathogenic ATP7B variant was detected, however, it is unknown whether these variants are in cis or trans (PMID: 27398169, 35222532, 36253962). This variant has been identified in 3/249588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 09, 2017)
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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: SCV000791002.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(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: SCV001455587.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Laboratory and clinical evaluation of a microarray for the detection of ATP7B mutations in Wilson disease in China. | Jia S | Journal of clinical laboratory analysis | 2022 | PMID: 36253962 |
Early Diagnosis of Wilson's Disease in Children in Southern China by Using Common Parameters. | Zhou J | Frontiers in genetics | 2022 | PMID: 35222532 |
Contribution of intragenic deletions to mutation spectrum in Chinese patients with Wilson's disease and possible mechanism underlying ATP7B gross deletions. | Chen YC | Parkinsonism & related disorders | 2019 | PMID: 30655162 |
Spectrum of ATP7B mutations and genotype-phenotype correlation in large-scale Chinese patients with Wilson Disease. | Cheng N | Clinical genetics | 2017 | PMID: 27982432 |
Mutational analysis of ATP7B in Chinese Wilson disease patients. | Hua R | American journal of translational research | 2016 | PMID: 27398169 |
Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. | Dong Y | Theranostics | 2016 | PMID: 27022412 |
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 |
Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease. | Zali N | Hepatitis monthly | 2011 | PMID: 22308153 |
Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort. | Lee BH | Liver international : official journal of the International Association for the Study of the Liver | 2011 | PMID: 21645214 |
Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. | Li XH | BMC medical genetics | 2011 | PMID: 21219664 |
Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system. | Hsi G | Human mutation | 2008 | PMID: 18203200 |
Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. | Lepori MB | Genetic testing | 2007 | PMID: 17949296 |
Sequence variation database for the Wilson disease copper transporter, ATP7B. | Kenney SM | Human mutation | 2007 | PMID: 17680703 |
Structure of the ATP binding domain from the Archaeoglobus fulgidus Cu+-ATPase. | Sazinsky MH | The Journal of biological chemistry | 2006 | PMID: 16495228 |
Wilson's Disease. | Ferenci P | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2005 | PMID: 16233999 |
The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. | Morgan CT | The Journal of biological chemistry | 2004 | PMID: 15205462 |
Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. | Loudianos G | Journal of medical genetics | 1999 | PMID: 10544227 |
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Text-mined citations for rs377297166 ...
HelpRecord last updated Sep 29, 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.