ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3914T>C (p.Leu1305Pro)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000053.4(ATP7B):c.3914T>C (p.Leu1305Pro)
Variation ID: 582922 Accession: VCV000582922.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51937383 (GRCh38) [ NCBI UCSC ] 13: 52511519 (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 Oct 10, 2018 Apr 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3914T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Leu1305Pro missense NM_001005918.3:c.3293T>C NP_001005918.1:p.Leu1098Pro missense NM_001243182.2:c.3581T>C NP_001230111.1:p.Leu1194Pro missense NM_001330578.2:c.3680T>C NP_001317507.1:p.Leu1227Pro missense NM_001330579.2:c.3662T>C NP_001317508.1:p.Leu1221Pro missense NC_000013.11:g.51937383A>G NC_000013.10:g.52511519A>G NG_008806.1:g.79112T>C - Protein change
- L1305P, L1221P, L1194P, L1227P, L1098P
- Other names
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- Canonical SPDI
- NC_000013.11:51937382:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 | - |
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
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 22, 2024 | RCV000707116.9 |
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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Pathogenic
(Jun 07, 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: SCV004216404.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 22, 2024)
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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: SCV000836199.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1305 of the ATP7B protein (p.Leu1305Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1305 of the ATP7B protein (p.Leu1305Pro). This variant is present in population databases (rs377144951, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11180609, 17272994, 19596473, 26819605). ClinVar contains an entry for this variant (Variation ID: 582922). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain Significance
(May 15, 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: SCV004844573.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces leucine with proline at codon 1305 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces leucine with proline at codon 1305 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Wilson disease in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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: 3
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Likely Pathogenic
(Jun 11, 2020)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847778.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Leu1305Pro variant in ATP7B has been previously reported in at least 5 individuals with Wilson disease, including 2 of which were compound heterozygous for … (more)
The p.Leu1305Pro variant in ATP7B has been previously reported in at least 5 individuals with Wilson disease, including 2 of which were compound heterozygous for the pathogenic p.His1069Gln variant and one who was compound heterozygous for p.Ala1135fs; though, it doesn't appear variants were phased (Folhoffer 2007 PMID 17272994; Posada 2017 abstract; Nemeth 2015 PMID 26819605, Genschel 2000 PMID 11180609). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. (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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Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease. | Németh D | Gastroenterology research and practice | 2016 | PMID: 26819605 |
Hepatocyte GP73 expression in Wilson disease. | Wright LM | Journal of hepatology | 2009 | PMID: 19596473 |
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 |
Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. | Folhoffer A | European journal of gastroenterology & hepatology | 2007 | PMID: 17272994 |
Three novel mutations (P760L, L1305P, Q1351Stop) causing Wilson disease. | Genschel J | Human mutation | 2001 | PMID: 11180609 |
Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake. | Wiesmann UN | Biochemical and biophysical research communications | 1975 | PMID: 4 |
Text-mined citations for rs377144951 ...
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.