ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.2998G>A (p.Gly1000Arg)
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.2998G>A (p.Gly1000Arg)
Variation ID: 557405 Accession: VCV000557405.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51946346 (GRCh38) [ NCBI UCSC ] 13: 52520482 (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 Apr 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.2998G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Gly1000Arg missense NM_001005918.3:c.2377G>A NP_001005918.1:p.Gly793Arg missense NM_001243182.2:c.2665G>A NP_001230111.1:p.Gly889Arg missense NM_001330578.2:c.2764G>A NP_001317507.1:p.Gly922Arg missense NM_001330579.2:c.2746G>A NP_001317508.1:p.Gly916Arg missense NC_000013.11:g.51946346C>T NC_000013.10:g.52520482C>T NG_008806.1:g.70149G>A - Protein change
- G1000R, G889R, G916R, G922R, G793R
- Other names
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- Canonical SPDI
- NC_000013.11:51946345: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) 0.00002
- Links
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 |
2850 | 2991 |
Conditions - Germline
Condition
Help
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000673544.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2023 | RCV003319396.1 |
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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Likely pathogenic
(Mar 23, 2018)
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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: SCV000798757.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely 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: SCV001977143.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(Feb 01, 2013)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: yes
Allele origin:
germline
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Arcensus
Accession: SCV002564616.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Oct 14, 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: SCV002780465.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 03, 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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GeneDx
Accession: SCV004023789.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Comment:
Published functional studies found this variant is unable to rescue growth of a yeast strain deficient for ccc2 (the ATP7B otholog in yeast) (Luoma LM … (more)
Published functional studies found this variant is unable to rescue growth of a yeast strain deficient for ccc2 (the ATP7B otholog in yeast) (Luoma LM et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16088907, 30120852, 20333758, 30275481, 22692182, 31708252, 23486543) (less)
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Pathogenic
(Dec 17, 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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Invitae
Accession: SCV000935825.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1000 of the ATP7B protein (p.Gly1000Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1000 of the ATP7B protein (p.Gly1000Arg). This variant is present in population databases (rs751078884, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 31059521). ClinVar contains an entry for this variant (Variation ID: 557405). 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: 20333758). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely 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: SCV004838323.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 1000 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glycine with arginine at codon 1000 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant alters a conserved glycine residue in the transmembrane M4 domain (a.a. 970 - 1003), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study has shown that this variant resulted in reduced ATP7B protein expression and altered protein function (PMID: 20333758). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 16088907, 30120852, 30702195, 31059521, 31708252, 33010844), including in one individual in the compound heterozygous state with a second pathogenic variant in the same gene (PMID: 30702195) and in the homozygous state in two individuals with no evidence of parental consanguinity (PMID: 30120852, 33010844). This variant has been identified in 9/244084 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant that results in the same amino acid change, c.2998G>C (p.Gly1000Arg), has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 23486543, 30230192), including in one individual in the compound heterozygous state with a second pathogenic variant in the ATP7B gene (PMID: 30230192). Based on the available evidence, this c.2998G>A (p.Gly1000Arg) variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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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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Structure of the Wilson disease copper transporter ATP7B. | Bitter RM | Science advances | 2022 | PMID: 35245129 |
Muscle stiffness, gait instability, and liver cirrhosis in Wilson's disease. | Kronlage C | Lancet (London, England) | 2020 | PMID: 33010844 |
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 |
Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. | Singh N | PloS one | 2019 | PMID: 31059521 |
Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. | Li X | Human mutation | 2019 | PMID: 30702195 |
Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype. | Kluska A | Liver international : official journal of the International Association for the Study of the Liver | 2019 | PMID: 30230192 |
Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications. | Kumari N | Human mutation | 2018 | PMID: 30120852 |
The homozygosity index (HI) approach reveals high allele frequency for Wilson disease in the Sardinian population. | Gialluisi A | European journal of human genetics : EJHG | 2013 | PMID: 23486543 |
Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. | Luoma LM | Human mutation | 2010 | PMID: 20333758 |
High incidence and allelic homogeneity of Wilson disease in 2 isolated populations: a prerequisite for efficient disease prevention programs. | Zappu A | Journal of pediatric gastroenterology and nutrition | 2008 | PMID: 18728530 |
Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. | Cox DW | Human mutation | 2005 | PMID: 16088907 |
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Text-mined citations for rs751078884 ...
HelpRecord last updated Apr 20, 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.