ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3818C>A (p.Pro1273Gln)
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.3818C>A (p.Pro1273Gln)
Variation ID: 553360 Accession: VCV000553360.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51937561 (GRCh38) [ NCBI UCSC ] 13: 52511697 (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 Feb 14, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3818C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Pro1273Gln missense NM_001005918.3:c.3197C>A NP_001005918.1:p.Pro1066Gln missense NM_001243182.2:c.3485C>A NP_001230111.1:p.Pro1162Gln missense NM_001330578.2:c.3584C>A NP_001317507.1:p.Pro1195Gln missense NM_001330579.2:c.3566C>A NP_001317508.1:p.Pro1189Gln missense NC_000013.11:g.51937561G>T NC_000013.10:g.52511697G>T NG_008806.1:g.78934C>A - Protein change
- P1273Q, P1195Q, P1066Q, P1162Q, P1189Q
- Other names
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- Canonical SPDI
- NC_000013.11:51937560:G: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00031
- 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 | ||
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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 |
2572 | 2712 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV000668789.11 |
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
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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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Likely pathogenic
(Aug 16, 2017)
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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: SCV000793447.1
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: SCV001977231.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Mar 07, 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: SCV002500148.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: ATP7B c.3818C>A (p.Pro1273Gln) 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.3818C>A (p.Pro1273Gln) 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 was absent in 249564 control chromosomes (gnomAD). c.3818C>A has been reported in the literature in two homozygous individuals affected with Wilson Disease (example: El-Mougy_2014) and the variant seggregated with the disease. These data indicate that the variant is likely to be associated with disease. Schushan_2012 demonstrated that P1273 changes to S/L/Q leads to very low copper uptake. Another variant affecting the same codon has been classified as pathogenic by our lab (p.Pro1273Leu). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 19, 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: SCV001222918.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1273 of the ATP7B protein (p.Pro1273Gln). … (more)
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1273 of the ATP7B protein (p.Pro1273Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 16696937, 18483695, 25465132, 27398169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553360). 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: 22692182). This variant disrupts the p.Pro1273 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024742, 17272994, 20485189, 23551039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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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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 |
Gene mutations in Wilson disease in Egyptian children: report on two novel mutations. | El-Mougy FA | Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology | 2014 | PMID: 25465132 |
Wilson disease mutation pattern with genotype-phenotype correlations from Western India: confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations. | Aggarwal A | Annals of human genetics | 2013 | PMID: 23551039 |
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 |
Six novel ATP7B mutations in Thai patients with Wilson disease. | Panichareon B | European journal of medical genetics | 2011 | PMID: 21034864 |
Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B. | Wan L | Hepatology (Baltimore, Md.) | 2010 | PMID: 20931554 |
Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. | Barada K | Journal of clinical gastroenterology | 2010 | PMID: 20485189 |
Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. | Abdelghaffar TY | Journal of human genetics | 2008 | PMID: 18483695 |
Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. | Mak CM | Journal of human genetics | 2008 | PMID: 18034201 |
Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. | Folhoffer A | European journal of gastroenterology & hepatology | 2007 | PMID: 17272994 |
Mutation analysis of Taiwanese Wilson disease patients. | Wan L | Biochemical and biophysical research communications | 2006 | PMID: 16696937 |
Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. | Deguti MM | Human mutation | 2004 | PMID: 15024742 |
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Text-mined citations for rs758355520 ...
HelpRecord last updated Feb 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.