ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.3646G>A (p.Val1216Met)
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.3646G>A (p.Val1216Met)
Variation ID: 188859 Accession: VCV000188859.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q14.3 13: 51939104 (GRCh38) [ NCBI UCSC ] 13: 52513240 (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 Mar 29, 2015 Apr 20, 2024 Jan 11, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000053.4:c.3646G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Val1216Met missense NM_001005918.3:c.3025G>A NP_001005918.1:p.Val1009Met missense NM_001243182.2:c.3313G>A NP_001230111.1:p.Val1105Met missense NM_001330578.2:c.3412G>A NP_001317507.1:p.Val1138Met missense NM_001330579.2:c.3394G>A NP_001317508.1:p.Val1132Met missense NC_000013.11:g.51939104C>T NC_000013.10:g.52513240C>T NG_008806.1:g.77391G>A P35670:p.Val1216Met - Protein change
- V1216M, V1105M, V1132M, V1138M, V1009M
- Other names
- -
- Canonical SPDI
- NC_000013.11:51939103:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00008
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 |
2850 | 2991 |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000169211.24 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2023 | RCV000725176.4 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158551.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The ATP7B c.3646G>A; p.Val1216Met variant (rs776280797) is reported in the literature in multiple individuals affected with Wilson disease (Haas 1999, Liu 2004, Loudianos 1998, Mak … (more)
The ATP7B c.3646G>A; p.Val1216Met variant (rs776280797) is reported in the literature in multiple individuals affected with Wilson disease (Haas 1999, Liu 2004, Loudianos 1998, Mak 2008, Margarit 2005, Qian 2019). Multiple affected individuals with this variant were also found to carry an additional pathogenic variant (Liu 2004, Margarit 2005, Qian 2019). The p.Val1216Met variant is found in the general population with the low overall allele frequency of 0.01% (24/280998 alleles) in the Genome Aggregation Database, and it is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 188859). The valine at codon 1216 is highly conserved, occurs in the functionally important ATP-binding loop (Loudianos 1998, Mak 2008), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Haas R et al. Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online. Hum Mutat. 1999;14(1):88. Liu XQ et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol. 2004 Feb 15;10(4):590-3. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. 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. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163728.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
Likely pathogenic
(Aug 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001977244.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
Pathogenic
(Nov 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766240.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: ATP7B c.3646G>A (p.Val1216Met) results in a conservative amino acid change located in the ATP-binding domain (Yuan_2015, Dong_2016) of the encoded protein sequence. Four … (more)
Variant summary: ATP7B c.3646G>A (p.Val1216Met) results in a conservative amino acid change located in the ATP-binding domain (Yuan_2015, Dong_2016) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 249592 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3646G>A has been reported in the literature as a biallelic genotype and as an uninformative genotype (second allele not reported/specified) in multiple individuals affected with Wilson Disease (e.g. Loudianos_1998, Haas_1999, Lee_2000, Margarit_2005, Park_2007, Yuan_2015, Balashova_2020) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=1) or likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Jul 02, 2014)
|
criteria provided, single submitter
Method: literature only
|
Wilson's disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220467.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Likely pathogenic
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004036652.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18034201, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18034201, 21219664, 31589614, 29637721, 18371106, 22692182, 30655162, 27022412, 34240825, 21645214, 17876883, 17587212, 20931554, 11043508, 8298641, 35220961, 26782526, 32618023, 9671269, 31708252, 30275481, 34324271, 35470480, 10447265, 14966923, 31172689, 26253413, 22677543, 30884209, 34620762, 27982432, 15952988) (less)
|
|
Pathogenic
(Nov 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001234718.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1216 of the ATP7B protein (p.Val1216Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1216 of the ATP7B protein (p.Val1216Met). This variant is present in population databases (rs776280797, gnomAD 0.07%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10447265, 14966923, 15952988, 26253413). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188859). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004828330.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 29637721, 30133932, 24253677). … (more)
Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 29637721, 30133932, 24253677). This variant has been reported in multiple individuals with Wilson disease and is one of the five most common pathogenic variants in the Chinese population (PMID: 35220961, 30884209, 26253413, 32618023, 26782526, 34324271, 31708252, 17876883, 34470610). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 35296237, 14966923). This gene has fewer missense variants in the general population than expected, which suggests that this gene is intolerant to missense variation. (less)
Number of individuals with the variant: 3
|
|
Likely pathogenic
(Aug 28, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000334638.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894014.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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 |
---|---|---|---|---|
Assessment of the diagnostic value of serum ceruloplasmin for Wilson's disease in children. | Lu X | BMC gastroenterology | 2022 | PMID: 35296237 |
Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China. | Zhang S | Translational neurodegeneration | 2022 | PMID: 35220961 |
Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. | Li M | BMC gastroenterology | 2021 | PMID: 34470610 |
Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. | Xiao Z | Molecular genetics & genomic medicine | 2021 | PMID: 34324271 |
Wilson's Disease in Finland: A Nationwide Population-Based Study. | Sipilä JOT | Movement disorders : official journal of the Movement Disorder Society | 2020 | PMID: 32618023 |
The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. | Balashova MS | Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) | 2020 | PMID: 31708252 |
Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. | Qian Z | Molecular genetics & genomic medicine | 2019 | PMID: 30884209 |
Only the tip of the Iceberg? Role of ATP7B-exon skipping in Wilson disease. | Rupp C | Liver international : official journal of the International Association for the Study of the Liver | 2018 | PMID: 30133932 |
Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease. | Wang C | Liver international : official journal of the International Association for the Study of the Liver | 2018 | PMID: 29637721 |
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 |
Analysis and application of ATP7B gene mutations in 35 patients with hepatolenticular degeneration. | Zong YN | Genetics and molecular research : GMR | 2015 | PMID: 26782526 |
Novel mutations of the ATP7B gene in Han Chinese families with pre-symptomatic Wilson's disease. | Yuan ZF | World journal of pediatrics : WJP | 2015 | PMID: 26253413 |
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 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 |
Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort. | Lee BH | Liver international : official journal of the International Association for the Study of the Liver | 2011 | PMID: 21645214 |
Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. | Li XH | BMC medical genetics | 2011 | PMID: 21219664 |
Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B. | Wan L | Hepatology (Baltimore, Md.) | 2010 | PMID: 20931554 |
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 |
Wilson disease: identification of two novel mutations and clinical correlation in Eastern Chinese patients. | Ye S | World journal of gastroenterology | 2007 | PMID: 17876883 |
Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. | Park S | Human mutation | 2007 | PMID: 17587212 |
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 |
Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. | Liu XQ | World journal of gastroenterology | 2004 | PMID: 14966923 |
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 in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online. | Haas R | Human mutation | 1999 | PMID: 10447265 |
Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. | Loudianos G | Human mutation | 1998 | PMID: 9671269 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP7B | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs776280797 ...
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.