This sequence change creates a premature translational stop signal (p.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000053.4(ATP7B):c.2009_2015del (p.Ile669_Tyr670insTer)
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.
(15)
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
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000053.4(ATP7B):c.2009_2015del (p.Ile669_Tyr670insTer)
Variation ID: 188862 Accession: VCV000188862.54
- Type and length
-
Deletion, 7 bp
- Location
-
Cytogenetic: 13q14.3 13: 51960254-51960260 (GRCh38) [ NCBI UCSC ] 13: 52534390-52534396 (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 Nov 24, 2024 Feb 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000053.4:c.2009_2015del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000044.2:p.Ile669_Tyr670insTer nonsense NM_001005918.3:c.1870-2653_1870-2647del intron variant NM_001243182.2:c.1676_1682del NP_001230111.1:p.Ile558_Tyr559insTer nonsense NM_001330578.2:c.2009_2015del NP_001317507.1:p.Ile669_Tyr670insTer nonsense NM_001330579.2:c.1870-1716_1870-1710del intron variant NC_000013.11:g.51960256_51960262del NC_000013.10:g.52534392_52534398del NG_008806.1:g.56235_56241del - Protein change
- -
- Other names
-
p.Tyr670*
- Canonical SPDI
- NC_000013.11:51960253:AGCATATAG:AG
-
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.
- -
- 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 |
2926 | 3070 | |
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 22, 2024 | RCV000169214.36 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV002274945.19 |
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
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001215891.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr670*) 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.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216331.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021994.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004362488.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159414.3
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas … (more)
The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170. (less)
|
|
|
Pathogenic
(Jun 11, 2020)
|
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: SCV004847858.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals … (more)
The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals from 2 families (Bull 1993, Thomas 1995, Curtis 1999). It has also been identified in 0.005% (6/112946) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188862). This deletion leads to a premature termination codon at position 670 , which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson Disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PM3, PP4. (less)
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033264.11
First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024 |
Comment:
ATP7B: PVS1, PP1:Strong, PM2, PM3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 03, 2017)
|
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: SCV000694412.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Comment:
Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense … (more)
Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002562346.2
First in ClinVar: Aug 23, 2022 Last updated: Mar 04, 2023 |
Comment:
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; Not … (more)
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7726170, 8298639, 10502777) (less)
|
|
|
Pathogenic
(Aug 15, 2023)
|
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: SCV004818840.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 6
|
|
|
Pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414185.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP4, PM2_moderate, PM3, PVS1
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 01, 1995)
|
no assertion criteria provided
Method: literature only
|
WILSON DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024213.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 29, 2020 |
Comment on evidence:
To confirm the conclusion that the gene they identified in a YAC from the 13q14.3 region and referred to as Wc1 was indeed the gene … (more)
To confirm the conclusion that the gene they identified in a YAC from the 13q14.3 region and referred to as Wc1 was indeed the gene mutated in Wilson disease (WND; 277900), Bull et al. (1993) studied 30 patients with the disorder selected to represent 29 different haplotypes based on 3 close markers. Using 3 cDNA fragments and 3 restriction enzymes, they found no altered fragments or dosage differences indicative of gross deletions. Single-strand conformation polymorphism analysis and heteroduplex analysis were performed in 27 patients. Both methods revealed a particular band shift, which on sequencing was found to represent homozygosity for the same 7-bp deletion, removing bases 1950-1956 of their sequence, causing a frameshift that resulted in an immediate stop codon at position 639 in the amino acid sequence, and removing the entire C-terminal half of the protein. The name of the 7-bp deletion (1950del7), originally described by Bull et al. (1993), was changed to 2010del7 to be consistent with the position of the ATG start codon identified by Petrukhin et al. (1994). The same mutation was found by Thomas et al. (1995) in affected members of 2 large kindreds in Iceland. Haplotype data and the nature of the mutation supported the existence of a founder chromosome. Although the protein function was predicted to be completely abolished by the deletion, predicting early-onset liver disease, Thomas et al. (1995) found that the patients presented with later-onset neurologic and psychiatric symptoms. They showed that alternative splicing of the transcript in the region of the deletion may have contributed to later onset, suggesting that alternative isoforms of the protein may have functional significance. (less)
|
|
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Pathogenic
(Aug 27, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002087856.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Feb 23, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Wilson disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220473.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Jul 21, 2023)
|
no assertion criteria provided
Method: research
|
Wilson disease
Affected status: yes
Allele origin:
germline
|
deCODE genetics, Amgen
Accession: SCV004022110.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a … (more)
The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. (less)
Number of individuals with the variant: 7
Ethnicity/Population group: Icelandic
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Comment:
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170.
Comment:
The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals from 2 families (Bull 1993, Thomas 1995, Curtis 1999). It has also been identified in 0.005% (6/112946) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188862). This deletion leads to a premature termination codon at position 670 , which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson Disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PM3, PP4.
Comment:
ATP7B: PVS1, PP1:Strong, PM2, PM3
Comment:
Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7726170, 8298639, 10502777)
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
PP4, PM2_moderate, PM3, PVS1
Comment:
The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies 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:
This sequence change creates a premature translational stop signal (p.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170.
Comment:
The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals from 2 families (Bull 1993, Thomas 1995, Curtis 1999). It has also been identified in 0.005% (6/112946) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188862). This deletion leads to a premature termination codon at position 670 , which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson Disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PM3, PP4.
Comment:
ATP7B: PVS1, PP1:Strong, PM2, PM3
Comment:
Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7726170, 8298639, 10502777)
Comment:
This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
PP4, PM2_moderate, PM3, PVS1
Comment:
The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The pathophysiology of Wilson's disease visualized: A human (64) Cu PET study. | Sandahl TD | Hepatology (Baltimore, Md.) | 2022 | PMID: 34773664 |
| Pediatric Pseudo-pseudoxanthoma Elasticum Resulting From D-Penicillamine Treatment for Wilson Disease. | Yu Z | Journal of pediatric gastroenterology and nutrition | 2020 | PMID: 32796424 |
| Reversal of Acute Liver Failure Due to Wilson Disease by a Regimen of High-Volume Plasma Exchange and Penicillamine. | Damsgaard J | Hepatology (Baltimore, Md.) | 2019 | PMID: 30357869 |
| 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 |
| A study of Wilson disease mutations in Britain. | Curtis D | Human mutation | 1999 | PMID: 10502777 |
| 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 |
| Wilson disease in Iceland: a clinical and genetic study. | Thomas GR | American journal of human genetics | 1995 | PMID: 7726170 |
| Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. | Petrukhin K | Human molecular genetics | 1994 | PMID: 7833924 |
| The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. | Bull PC | Nature genetics | 1993 | PMID: 8298639 |
Text-mined citations for rs779904655 ...
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Record last updated Nov 25, 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.