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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. ClinVar contains an entry for this variant (Variation ID: 555650). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 25089800, 27022412, 29321352, 31059521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778543794, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1052 of the ATP7B protein (p.Pro1052Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481).
ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3155C>T (p.Pro1052Leu)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000053.4(ATP7B):c.3155C>T (p.Pro1052Leu)
Variation ID: 555650 Accession: VCV000555650.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q14.3 13: 51944197 (GRCh38) [ NCBI UCSC ] 13: 52518333 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 16, 2024 Feb 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000053.4:c.3155C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Pro1052Leu missense NM_001005918.3:c.2534C>T NP_001005918.1:p.Pro845Leu missense NM_001243182.2:c.2822C>T NP_001230111.1:p.Pro941Leu missense NM_001330578.2:c.2921C>T NP_001317507.1:p.Pro974Leu missense NM_001330579.2:c.2903C>T NP_001317508.1:p.Pro968Leu missense NC_000013.11:g.51944197G>A NC_000013.10:g.52518333G>A NG_008806.1:g.72298C>T - Protein change
- P1052L, P941L, P974L, P845L, P968L
- Other names
- -
- Canonical SPDI
- NC_000013.11:51944196:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| ATP7B | - | - |
GRCh38 GRCh37 |
2916 | 3060 | |
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
Help
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000671512.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 13, 2024 | RCV004702300.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001977139.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Likely pathogenic
(Mar 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216445.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000947086.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. ClinVar contains an entry for this variant (Variation ID: 555650). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 25089800, 27022412, 29321352, 31059521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778543794, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1052 of the ATP7B protein (p.Pro1052Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481). (less)
|
|
|
Likely pathogenic
(Feb 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201657.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Published functional studies found this variant is associated with significantly impaired copper transport (PMID: 22240481); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies found this variant is associated with significantly impaired copper transport (PMID: 22240481); 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: 35782615, 29321352, 31059521, 23518715, 34470610, 36047117, 30275481, 10502777, 25089800, 27022412, 24253677, 22692182, 22240481) (less)
|
|
|
Uncertain significance
(Dec 28, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000796496.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Published functional studies found this variant is associated with significantly impaired copper transport (PMID: 22240481); 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: 35782615, 29321352, 31059521, 23518715, 34470610, 36047117, 30275481, 10502777, 25089800, 27022412, 24253677, 22692182, 22240481)
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. |
Comment:
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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. ClinVar contains an entry for this variant (Variation ID: 555650). This missense change has been observed in individual(s) with Wilson disease (PMID: 10502777, 25089800, 27022412, 29321352, 31059521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778543794, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1052 of the ATP7B protein (p.Pro1052Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481).
Comment:
Published functional studies found this variant is associated with significantly impaired copper transport (PMID: 22240481); 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: 35782615, 29321352, 31059521, 23518715, 34470610, 36047117, 30275481, 10502777, 25089800, 27022412, 24253677, 22692182, 22240481)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. | Singh N | PloS one | 2019 | PMID: 31059521 |
| Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. | Tuan Pham LA | Journal of genetics | 2017 | PMID: 29321352 |
| 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 |
| Mutational characterization of ATP7B gene in 103 Wilson's disease patients from Southern China: identification of three novel mutations. | Wei Z | Neuroreport | 2014 | PMID: 25089800 |
| 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 |
| A genetic study of Wilson's disease in the United Kingdom. | Coffey AJ | Brain : a journal of neurology | 2013 | PMID: 23518715 |
| 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 |
| A study of Wilson disease mutations in Britain. | Curtis D | Human mutation | 1999 | PMID: 10502777 |
Text-mined citations for rs778543794 ...
HelpThese 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 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.