ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3955C>T (p.Arg1319Ter)
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
-
NM_000053.4(ATP7B):c.3955C>T (p.Arg1319Ter)
Variation ID: 35728 Accession: VCV000035728.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q14.3 13: 51937342 (GRCh38) [ NCBI UCSC ] 13: 52511478 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Mar 10, 2024 Jan 18, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000053.4:c.3955C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Arg1319Ter nonsense NM_001005918.3:c.3334C>T NP_001005918.1:p.Arg1112Ter nonsense NM_001243182.2:c.3622C>T NP_001230111.1:p.Arg1208Ter nonsense NM_001330578.2:c.3721C>T NP_001317507.1:p.Arg1241Ter nonsense NM_001330579.2:c.3703C>T NP_001317508.1:p.Arg1235Ter nonsense NC_000013.11:g.51937342G>A NC_000013.10:g.52511478G>A NG_008806.1:g.79153C>T - Protein change
- R1319*, R1112*, R1208*, R1235*, R1241*
- Other names
- -
- Canonical SPDI
- NC_000013.11:51937341:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
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 |
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
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 (12) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000029377.44 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 29, 2022 | RCV000494120.26 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 1, 2015 | RCV002371783.2 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000192356.1
First in ClinVar: Nov 22, 2014 Last updated: Nov 22, 2014 |
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611175.1
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
|
|
Pathogenic
(Apr 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602617.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 05, 2022 |
Comment:
The ATP7B c.3955C>T; p.Arg1319Ter variant (rs193922109) is described in the medical literature as homozygous or in combination with other pathogenic variants in individuals with Wilson … (more)
The ATP7B c.3955C>T; p.Arg1319Ter variant (rs193922109) is described in the medical literature as homozygous or in combination with other pathogenic variants in individuals with Wilson disease (Abdelghaffar 2008, Balashova 2020, Deguti 2004, Margarit 2005, Waldenstrom 1996). This variant is found in the general population with an overall allele frequency of 0.007% (20/280972 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Abdelghaffar TY et al. Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet. 2008;53(8):681. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. (less)
|
|
Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582410.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22774841, 8938442, 11472373, 7626145, 8533760, 10544227, 19118915, 18483695, 25497208, 34240825, 25525159, 18371106, 31708252, 34324271, 23333878, 27022412, 23518715, 21796144, 21682854, 20967755, 18034201, 16283883, 31589614, 30556376, 30291343, 32513368) (less)
|
|
Pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216292.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003811212.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000626862.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1319*) in the ATP7B gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1319*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs193922109, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 893844, 7626145, 15024742, 15952988, 18483695, 21682854, 21796144, 23518715, 27022412). ClinVar contains an entry for this variant (Variation ID: 35728). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063104.13
First in ClinVar: Jan 29, 2022 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Apr 20, 2021)
|
criteria provided, single submitter
Method: research
|
Wilson disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV001571614.1
First in ClinVar: Apr 23, 2021 Last updated: Apr 23, 2021 |
Comment:
The p.Arg1319* nonsense variant in ATP7B is a well-established pathogenic variant and has been reported in numerous patients to date. It is present at very … (more)
The p.Arg1319* nonsense variant in ATP7B is a well-established pathogenic variant and has been reported in numerous patients to date. It is present at very low frequency in the gnomAD database (MAF<0.0001) and is predicted to truncate a significant portion of the protein. Multiple reputable laboratories have recently reported it as pathogenic. We interpret the variant as pathogenic. We identified this variant in a proband with clinical Wilson's disease; it was in compound-heterozygous state with a synonymous change (p.Leu1015=) shown to cause exon skipping by research RNA-seq. In that same experiment, we observed that the p.Arg1319* variant was present in <25% of RNA reads, suggesting that variant transcripts are subject to nonsense-mediated decay. (less)
Comment on evidence:
Compound-heterozygous with a synonymous variant shown to disrupt splicing in a patient with clinically confirmed WD.
|
|
Pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001977222.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
Wilson Disease
(autosomal recessive)
Affected status: unknown, yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052025.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 4
Observation 3:
Number of individuals with the variant: 2
Observation 4:
Number of individuals with the variant: 7
Observation 5:
Number of individuals with the variant: 6
Observation 6:
Tissue: Blood
|
|
Pathogenic
(May 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002624018.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R1319* pathogenic mutation (also known as c.3955C>T and p.R1319X), located in coding exon 19 of the ATP7B gene, results from a C to T … (more)
The p.R1319* pathogenic mutation (also known as c.3955C>T and p.R1319X), located in coding exon 19 of the ATP7B gene, results from a C to T substitution at nucleotide position 3955. This changes the amino acid from an arginine to a stop codon within coding exon 19. This mutation was identified in the homozygous state in four patients with a clinical diagnosis of Wilson disease and who exhibited lower serum copper levels (Nicastro E et al. J Hepatol. 2009;50(3):555-61). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746793.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022 |
Age: 20-29 years
Sex: female
Geographic origin: Iran
|
|
Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713628.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PM2, PVS1
Number of individuals with the variant: 7
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455575.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
Pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220371.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
click to load more click to collapse |
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
loss_of_function_variant
|
|
|
Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV001571614.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
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 |
A genetic study of Wilson's disease in the United Kingdom. | Coffey AJ | Brain : a journal of neurology | 2013 | PMID: 23518715 |
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 |
Phenotypic and genetic characterization of a cohort of pediatric Wilson disease patients. | Abdel Ghaffar TY | BMC pediatrics | 2011 | PMID: 21682854 |
Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. | Nicastro E | Hepatology (Baltimore, Md.) | 2010 | PMID: 20967755 |
Genotype-phenotype correlation in Italian children with Wilson's disease. | Nicastro E | Journal of hepatology | 2009 | PMID: 19118915 |
Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. | Abdelghaffar TY | Journal of human genetics | 2008 | PMID: 18483695 |
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 |
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 |
Neurological manifestations and ATP7B mutations in Wilson's disease. | Machado AA | Parkinsonism & related disorders | 2008 | PMID: 17897870 |
Different neurological outcome of liver transplantation for Wilson's disease in two homozygotic twins. | Senzolo M | Clinical neurology and neurosurgery | 2007 | PMID: 16545904 |
Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease. | Gromadzka G | Clinical genetics | 2005 | PMID: 16283883 |
Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. | Margarit E | Clinical genetics | 2005 | PMID: 15952988 |
Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. | Deguti MM | Human mutation | 2004 | PMID: 15024742 |
Haemolytic onset of Wilson disease in a patient with homozygous truncation of ATP7B at Arg1319. | Prella M | British journal of haematology | 2001 | PMID: 11472373 |
Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. | Loudianos G | Journal of medical genetics | 1999 | PMID: 10544227 |
Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. | Buiakova OI | Human molecular genetics | 1999 | PMID: 10441329 |
Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. | Shah AB | American journal of human genetics | 1997 | PMID: 9311736 |
Efficient detection of mutations in Wilson disease by manifold sequencing. | Waldenström E | Genomics | 1996 | PMID: 8938442 |
Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. | Figus A | American journal of human genetics | 1995 | PMID: 8533760 |
The Wilson disease gene: spectrum of mutations and their consequences. | Thomas GR | Nature genetics | 1995 | PMID: 7626145 |
Extraction of important molecular features of musk compounds using pattern recognition techniques. | Brugger WE | Journal of agricultural and food chemistry | 1977 | PMID: 893844 |
click to load more click to collapse |
Text-mined citations for rs193922109 ...
HelpRecord last updated Mar 17, 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.