ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3426G>C (p.Gln1142His)
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.
Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000053.4(ATP7B):c.3426G>C (p.Gln1142His)
Variation ID: 370151 Accession: VCV000370151.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 51941211 (GRCh38) [ NCBI UCSC ] 13: 52515347 (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 Jan 6, 2017 Nov 4, 2023 Sep 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000053.4:c.3426G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Gln1142His missense NM_001005918.3:c.2805G>C NP_001005918.1:p.Gln935His missense NM_001243182.2:c.3093G>C NP_001230111.1:p.Gln1031His missense NM_001330578.2:c.3192G>C NP_001317507.1:p.Gln1064His missense NM_001330579.2:c.3174G>C NP_001317508.1:p.Gln1058His missense NC_000013.11:g.51941211C>G NC_000013.10:g.52515347C>G NG_008806.1:g.75284G>C - Protein change
- Q1142H, Q935H, Q1058H, Q1064H, Q1031H
- Other names
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- Canonical SPDI
- NC_000013.11:51941210: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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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
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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 |
2578 | 2719 |
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 (3) |
criteria provided, conflicting classifications
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Aug 10, 2021 | RCV000409630.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 28, 2023 | RCV002469139.2 |
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
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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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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: SCV001977554.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(Dec 02, 2015)
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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: SCV000485394.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Mar 09, 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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Invitae
Accession: SCV000934021.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamine with histidine at codon 1142 of the ATP7B protein (p.Gln1142His). The glutamine residue is weakly conserved and there is a … (more)
This sequence change replaces glutamine with histidine at codon 1142 of the ATP7B protein (p.Gln1142His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs778749563, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Wilson disease (PMID: 11405812). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It has also been reported in other unrelated affected individuals (PMID: 26483271, 11043508, 9829905) although in some of these individuals another variant was identified in the same allele. ClinVar contains an entry for this variant (Variation ID: 370151). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
(Sep 28, 2023)
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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: SCV002766260.2
First in ClinVar: Dec 24, 2022 Last updated: Nov 04, 2023 |
Comment:
Variant summary: ATP7B c.3426G>C (p.Gln1142His) 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.3426G>C (p.Gln1142His) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249588 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3426G>C has been reported in the literature in individuals, particularly of Eastern Asian descent, affected with Wilson Disease; however, a lot of the studies (especially recent ones with comprehensively genotyped patients), report the variant to co-occur in cis with the known pathogenic variant c.3443T>C (p.Ile1148Thr) (e.g. Tsai_1998, Lee_200, Wu_2001, Wu_2003, Mak_2008, Wang_2011, Coffey_2013, Dong_2016, Poon_2016, Hou_2022, Li_2021_Zhang_2022). In support of this observation, control data indicate these two variants are likely found on the same haplotype in most individuals in gnomAD. These data do not allow any conclusion about the significance of the p.Gln1142His variant on its own. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23518715, 27022412, 35079019, 11043508, 18034201, 26483271, 9829905, 21796144, 11405812, 12756138, 34470610, 35220961). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (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 and genetic characterization of a large cohort of patients with Wilson's disease in China. | Zhang S | Translational neurodegeneration | 2022 | PMID: 35220961 |
A capillary electrophoresis-based multiplex PCR assay for expanded carrier screening in the eastern Han Chinese population. | Hu P | NPJ genomic medicine | 2022 | PMID: 35079019 |
Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. | Li M | BMC gastroenterology | 2021 | PMID: 34470610 |
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 |
Targeted next-generation sequencing of the ATP7B gene for molecular diagnosis of Wilson disease. | Poon KS | Clinical biochemistry | 2016 | PMID: 26483271 |
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 |
Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. | Wang LH | Journal of human genetics | 2011 | PMID: 21796144 |
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 |
Molecular diagnosis and prophylactic therapy for presymptomatic Chinese patients with Wilson disease. | Wu ZY | Archives of neurology | 2003 | PMID: 12756138 |
Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. | Wu ZY | Archives of neurology | 2001 | PMID: 11405812 |
Molecular analysis of Wilson disease in Taiwan: identification of one novel mutation and evidence of haplotype-mutation association. | Lee CC | Journal of human genetics | 2000 | PMID: 11043508 |
Mutation analysis of Wilson disease in Taiwan and description of six new mutations. | Tsai CH | Human mutation | 1998 | PMID: 9829905 |
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Text-mined citations for rs778749563 ...
HelpRecord last updated Feb 04, 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.