PS4_moderate, PM2, PM3, PP3, PP4
ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.1924G>C (p.Asp642His)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Genotype
- Identifiers
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NM_000053.4(ATP7B):c.1924G>C (p.Asp642His)
Variation ID: 189109 Accession: VCV000189109.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51961859 (GRCh38) [ NCBI UCSC ] 13: 52535995 (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 29, 2015 Jun 17, 2024 Mar 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000053.4:c.1924G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Asp642His missense NM_001005918.3:c.1869+3013G>C intron variant NM_001243182.2:c.1591G>C NP_001230111.1:p.Asp531His missense NM_001330578.2:c.1924G>C NP_001317507.1:p.Asp642His missense NM_001330579.2:c.1869+3013G>C intron variant NC_000013.11:g.51961859C>G NC_000013.10:g.52535995C>G NG_008806.1:g.54636G>C P35670:p.Asp642His - Protein change
- D642H, D531H
- Other names
- -
- Canonical SPDI
- NC_000013.11:51961858:C: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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effect on protein subcellular localization; Variation Ontology [ VariO:0033]
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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
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
2915 | 3059 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000169521.23 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 26, 2020 | RCV001508348.6 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Aug 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714453.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4_moderate, PM2, PM3, PP3, PP4
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(Dec 29, 2014)
|
criteria provided, single submitter
Method: literature only
|
Wilson's disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220995.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
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Likely pathogenic
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813833.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Likely pathogenic
(May 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024426.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
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Wilson disease
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805055.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Likely Pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848316.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Asp642His variant in ATP7B has been reported in at least 4 homozygous and 1 compound heterozygous patients with Wilson disease (Abdel Ghaffar 2011 PMID: … (more)
The p.Asp642His variant in ATP7B has been reported in at least 4 homozygous and 1 compound heterozygous patients with Wilson disease (Abdel Ghaffar 2011 PMID: 18483695, Moller 2011 PMID: 21610751, Braiterman 2014 PMID: 24706876, Daneshjoo 2018 PMID: 29540233). It has also segregated in an affected relative (Daneshjoo 2018 PMID: 29540233). It has been identified in 2/34528 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this is low enough to be consistent with a recessive allele frequency. Several functional studies indicated that this missense variant behaved similar to wild-type (Hsi 2008 PMID: 18203200); however, these types of assays may not accurately represent biological function. 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; however, studies are required to determine that this variant is located on the functional gene, not pseudogene. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1, PP4. (less)
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Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216321.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jul 22, 2021)
|
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: SCV001810287.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000626833.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 642 of the ATP7B protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 642 of the ATP7B protein (p.Asp642His). This variant is present in population databases (rs72552285, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson syndrome and a copper metabolism disorder and Wilson disease (PMID: 18483695, 21610751, 21682854, 22308153, 24706876, 29540233; 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. ClinVar contains an entry for this variant (Variation ID: 189109). 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 not expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 18203200). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 02, 2021)
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no assertion criteria provided
Method: clinical testing
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Wilson disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002087859.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The p.Asp642His variant in ATP7B has been reported in at least 4 homozygous and 1 compound heterozygous patients with Wilson disease (Abdel Ghaffar 2011 PMID: 18483695, Moller 2011 PMID: 21610751, Braiterman 2014 PMID: 24706876, Daneshjoo 2018 PMID: 29540233). It has also segregated in an affected relative (Daneshjoo 2018 PMID: 29540233). It has been identified in 2/34528 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this is low enough to be consistent with a recessive allele frequency. Several functional studies indicated that this missense variant behaved similar to wild-type (Hsi 2008 PMID: 18203200); however, these types of assays may not accurately represent biological function. 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; however, studies are required to determine that this variant is located on the functional gene, not pseudogene. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1, PP4.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 642 of the ATP7B protein (p.Asp642His). This variant is present in population databases (rs72552285, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson syndrome and a copper metabolism disorder and Wilson disease (PMID: 18483695, 21610751, 21682854, 22308153, 24706876, 29540233; 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. ClinVar contains an entry for this variant (Variation ID: 189109). 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 not expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 18203200). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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:
PS4_moderate, PM2, PM3, PP3, PP4
Comment:
The p.Asp642His variant in ATP7B has been reported in at least 4 homozygous and 1 compound heterozygous patients with Wilson disease (Abdel Ghaffar 2011 PMID: 18483695, Moller 2011 PMID: 21610751, Braiterman 2014 PMID: 24706876, Daneshjoo 2018 PMID: 29540233). It has also segregated in an affected relative (Daneshjoo 2018 PMID: 29540233). It has been identified in 2/34528 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), though this is low enough to be consistent with a recessive allele frequency. Several functional studies indicated that this missense variant behaved similar to wild-type (Hsi 2008 PMID: 18203200); however, these types of assays may not accurately represent biological function. 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; however, studies are required to determine that this variant is located on the functional gene, not pseudogene. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1, PP4.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 642 of the ATP7B protein (p.Asp642His). This variant is present in population databases (rs72552285, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson syndrome and a copper metabolism disorder and Wilson disease (PMID: 18483695, 21610751, 21682854, 22308153, 24706876, 29540233; 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. ClinVar contains an entry for this variant (Variation ID: 189109). 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 not expected to disrupt ATP7B protein function. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 18203200). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report. | Daneshjoo O | Journal of medical case reports | 2018 | PMID: 29540233 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| 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 |
| Prevalence of ATP7B Gene Mutations in Iranian Patients With Wilson Disease. | Zali N | Hepatitis monthly | 2011 | PMID: 22308153 |
| Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. | Abdel Ghaffar TY | BMC pediatrics | 2011 | PMID: 21682854 |
| Clinical presentation and mutations in Danish patients with Wilson disease. | Møller LB | European journal of human genetics : EJHG | 2011 | PMID: 21610751 |
| Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. | Abdelghaffar TY | Journal of human genetics | 2008 | PMID: 18483695 |
| Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system. | Hsi G | Human mutation | 2008 | PMID: 18203200 |
| 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 |
| Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. | Loudianos G | Human mutation | 1998 | PMID: 9671269 |
Text-mined citations for rs72552285 ...
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 Oct 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.