ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.1922T>C (p.Leu641Ser)
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.
Uncertain significance(10); Likely benign(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.1922T>C (p.Leu641Ser)
Variation ID: 420002 Accession: VCV000420002.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51961861 (GRCh38) [ NCBI UCSC ] 13: 52535997 (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 Mar 17, 2018 Apr 15, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.1922T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Leu641Ser missense NM_001005918.3:c.1869+3011T>C intron variant NM_001243182.2:c.1589T>C NP_001230111.1:p.Leu530Ser missense NM_001330578.2:c.1922T>C NP_001317507.1:p.Leu641Ser missense NM_001330579.2:c.1869+3011T>C intron variant NC_000013.11:g.51961861A>G NC_000013.10:g.52535997A>G NG_008806.1:g.54634T>C - Protein change
- L641S, L530S
- Other names
- -
- Canonical SPDI
- NC_000013.11:51961860: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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0.00040 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00033
Exome Aggregation Consortium (ExAC) 0.00039
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00049
The Genome Aggregation Database (gnomAD) 0.00059
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00067
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 |
2578 | 2719 |
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. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2022 | RCV000587060.27 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000631248.28 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 14, 2021 | RCV001263514.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 30, 2022 | RCV002525825.2 |
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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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001267853.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440937.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
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Uncertain significance
(May 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694407.3
First in ClinVar: Mar 17, 2018 Last updated: May 23, 2021 |
Comment:
Variant summary: ATP7B c.1922T>C (p.Leu641Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ATP7B c.1922T>C (p.Leu641Ser) results in a non-conservative amino acid change in 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 0.0005 in 251632 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0005 vs 0.0054), allowing no conclusion about variant significance. The variant c.1922T>C has been reported in the literature in individuals affected with Wilson Disease (example: Cox_2005, Vrabelova_2005, Bost_2012, Ferenci_2019), however, in most of these cases no full gene sequencing was performed, and/or the other pathogenic variant in trans was not specified and/or phase was not provided. These data therefore do not allow clear conclusions about the variant significance. Publications also reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein localization, copper transport activity, and copper-responsive trafficking (Braiterman_2014) and no effect on interaction with COMMD1 (de Bie_2007). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714454.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(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: SCV001977178.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Uncertain significance
(Nov 08, 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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Myriad Genetics, Inc.
Accession: SCV002060319.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000053.3(ATP7B):c.1922T>C(L641S) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. L641S has been observed in cases with … (more)
NM_000053.3(ATP7B):c.1922T>C(L641S) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. L641S has been observed in cases with relevant disease (PMID: 30232804, 15967699, 16088907, 22677543). Functional assessments of this variant are available in the literature (PMID: 24706876, 17919502). L641S has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.1922T>C(L641S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Uncertain significance
(Sep 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003675423.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.1922T>C (p.L641S) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a T to C substitution … (more)
The c.1922T>C (p.L641S) alteration is located in exon 6 (coding exon 6) of the ATP7B gene. This alteration results from a T to C substitution at nucleotide position 1922, causing the leucine (L) at amino acid position 641 to be replaced by a serine (S). The altered amino acid is conserved throughout evolution: The p.L641 amino acid is conserved in available vertebrate species. The p.L641S alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 20, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473412.4
First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023 |
Comment:
The ATP7B c.1922T>C; p.Leu641Ser variant (rs186924074) is reported in the literature in individuals affected with Wilson disease (Bost 2012, Coffey 2013, Cox 2005, Vrabelova 2005). … (more)
The ATP7B c.1922T>C; p.Leu641Ser variant (rs186924074) is reported in the literature in individuals affected with Wilson disease (Bost 2012, Coffey 2013, Cox 2005, Vrabelova 2005). This variant is reported in ClinVar (Variation ID: 420002), and is found in the general population with an overall allele frequency of 0.046% (130/280986 alleles) in the Genome Aggregation Database. The leucine at codon 641 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.93). However, functional analyses of the variant protein show similar copper trafficking compared to wild type (Braiterman 2014, de Bie 2007). Due to conflicting information, the clinical significance of the p.Leu641Ser variant is uncertain at this time. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012;26(2-3):97-101. PMID: 22677543. Braiterman LT et al. Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. Proc Natl Acad Sci U S A. 2014;111(14):E1364-E1373. PMID: 24706876. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013;136(Pt 5):1476-1487. PMID: 23518715. Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005;26(3):280. PMID: 16088907. de Bie P et al. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. Gastroenterology. 2007;133(4):1316-1326. PMID: 17919502. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005;86(1-2):277-285. PMID: 15967699. (less)
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Uncertain significance
(Dec 16, 2022)
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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: SCV000568298.6
First in ClinVar: Apr 27, 2017 Last updated: May 27, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated that p.(L641S) behaved similarly to the … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated that p.(L641S) behaved similarly to the wild-type protein (de Bie et al. 2007; Braiterman et al. 2014); This variant is associated with the following publications: (PMID: 15967699, 23518715, 17919502, 18371106, 22677543, 24253677, 30097039, 34426522, 32248359, 16088907, Cumpata2022[Review], 24706876, 34400371, 36096368, 34620762, 35132767) (less)
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Uncertain significance
(Jan 29, 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: SCV000752272.6
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 641 of the ATP7B protein (p.Leu641Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 641 of the ATP7B protein (p.Leu641Ser). This variant is present in population databases (rs186924074, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 15967699, 16088907, 22677543, 23518715, 34400371). ClinVar contains an entry for this variant (Variation ID: 420002). 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. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 17919502, 24706876). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248429.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 3
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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 |
ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. | Wallace DF | Human genetics | 2020 | PMID: 32248359 |
The Prevalence of Wilson's Disease: An Update. | Sandahl TD | Hepatology (Baltimore, Md.) | 2020 | PMID: 31449670 |
Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease. | Ferenci P | Hepatology (Baltimore, Md.) | 2019 | PMID: 30232804 |
High genetic carrier frequency of Wilson's disease in France: discrepancies with clinical prevalence. | Collet C | BMC medical genetics | 2018 | PMID: 30097039 |
Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B. | Braiterman LT | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 24706876 |
A genetic study of Wilson's disease in the United Kingdom. | Coffey AJ | Brain : a journal of neurology | 2013 | PMID: 23518715 |
Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. | Bost M | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2012 | PMID: 22677543 |
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 |
Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. | de Bie P | Gastroenterology | 2007 | PMID: 17919502 |
Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. | Cox DW | Human mutation | 2005 | PMID: 16088907 |
Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. | Vrabelova S | Molecular genetics and metabolism | 2005 | PMID: 15967699 |
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Text-mined citations for rs186924074 ...
HelpRecord last updated Apr 15, 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.