ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3659C>T (p.Thr1220Met)
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.3659C>T (p.Thr1220Met)
Variation ID: 35725 Accession: VCV000035725.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51939091 (GRCh38) [ NCBI UCSC ] 13: 52513227 (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 Apr 4, 2013 Apr 20, 2024 Nov 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3659C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Thr1220Met missense NM_001005918.3:c.3038C>T NP_001005918.1:p.Thr1013Met missense NM_001243182.2:c.3326C>T NP_001230111.1:p.Thr1109Met missense NM_001330578.2:c.3425C>T NP_001317507.1:p.Thr1142Met missense NM_001330579.2:c.3407C>T NP_001317508.1:p.Thr1136Met missense NC_000013.11:g.51939091G>A NC_000013.10:g.52513227G>A NG_008806.1:g.77404C>T P35670:p.Thr1220Met - Protein change
- T1220M, T1142M, T1013M, T1136M, T1109M
- Other names
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- Canonical SPDI
- NC_000013.11:51939090:G:A
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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 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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
Help
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
Help
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 (8) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2023 | RCV000029374.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 9, 2020 | RCV000413521.2 |
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
(Sep 09, 2020)
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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: SCV000491163.2
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
Published functional studies demonstrate that site-directed mutagenesis of the residues in the ATP-binding domain found that alteration of this sequence abolishes calcium transport activity (Loudianos … (more)
Published functional studies demonstrate that site-directed mutagenesis of the residues in the ATP-binding domain found that alteration of this sequence abolishes calcium transport activity (Loudianos et al. 1996); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 16283883, 17949296, 22763723, 20931554, 25497208, 24661374, 30275481, 22692182, 21610751, 23774950, 8931691, 31708252, 31400605) (less)
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Likely pathogenic
(Jun 29, 2014)
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criteria provided, single submitter
Method: literature only
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Wilson's disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220459.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(May 03, 2022)
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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: SCV000611172.2
First in ClinVar: May 27, 2015 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 01, 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: SCV004216311.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 05, 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: SCV000940902.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1220 of the ATP7B protein (p.Thr1220Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1220 of the ATP7B protein (p.Thr1220Met). This variant is present in population databases (rs193922107, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21610751, 22763723, 24661374, 25497208; Invitae). ClinVar contains an entry for this variant (Variation ID: 35725). 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
(Oct 02, 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: SCV004845316.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 1220 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with methionine at codon 1220 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). This variant has been observed in the compound heterozygous state in many individuals affected with autosomal recessive Wilson disease (PMID: 8931691, 10447265, 16283883, 17949296, 18371106, 18483695, 19371217, 20967755, 21610751, 22763723, 23518715, 24661374, 25497208, 34400371), indicating that this variant contributes to disease. This variant has been identified in 1/249594 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: 3
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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: SCV001977242.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Aug 10, 2022)
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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: SCV000052022.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2022 |
Comment:
Variant summary: ATP7B c.3659C>T (p.Thr1220Met) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein … (more)
Variant summary: ATP7B c.3659C>T (p.Thr1220Met) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249960 control chromosomes (gnomAD and Loudianos_1996, Abdelghaffar_2008). c.3659C>T has been reported in the literature in many individuals affected with Wilson Disease (e.g. Loudianos_1996, Haas_1999, Gromadzka_2005, Lepori_2007, Gojova_2008, Abdelghaffar_2008, Lovicu_2009, Moller_2011). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 12, 2021)
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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: SCV002086799.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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 variant spectrum in a French pediatric Wilson disease cohort. | Couchonnal E | European journal of medical genetics | 2021 | PMID: 34400371 |
Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins. | Paradisi I | European journal of medical genetics | 2015 | PMID: 25497208 |
Zinc monotherapy is effective in Wilson's disease patients with mild liver disease diagnosed in childhood: a retrospective study. | Ranucci G | Orphanet journal of rare diseases | 2014 | PMID: 24661374 |
A genetic study of Wilson's disease in the United Kingdom. | Coffey AJ | Brain : a journal of neurology | 2013 | PMID: 23518715 |
Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study. | Hofer H | Journal of human genetics | 2012 | PMID: 22763723 |
Clinical presentation and mutations in Danish patients with Wilson disease. | Møller LB | European journal of human genetics : EJHG | 2011 | PMID: 21610751 |
Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. | Nicastro E | Hepatology (Baltimore, Md.) | 2010 | PMID: 20967755 |
RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease. | Lovicu M | Genetic testing and molecular biomarkers | 2009 | PMID: 19371217 |
Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. | Abdelghaffar TY | Journal of human genetics | 2008 | PMID: 18483695 |
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 |
Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. | Lepori MB | Genetic testing | 2007 | PMID: 17949296 |
Structure of the ATP binding domain from the Archaeoglobus fulgidus Cu+-ATPase. | Sazinsky MH | The Journal of biological chemistry | 2006 | PMID: 16495228 |
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 |
Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations. | Efremov RG | The Biochemical journal | 2004 | PMID: 15147237 |
Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online. | Haas R | Human mutation | 1999 | PMID: 10447265 |
Wilson disease mutations associated with uncommon haplotypes in Mediterranean patients. | Loudianos G | Human genetics | 1996 | PMID: 8931691 |
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Text-mined citations for rs193922107 ...
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.