NM_000053.4(ATP7B):c.3061-1G>A AND Wilson disease
- Germline classification:
- Pathogenic (4 submissions)
- Last evaluated:
- Feb 2, 2023
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV002037652.6
Allele description [Variation Report for NM_000053.4(ATP7B):c.3061-1G>A]
NM_000053.4(ATP7B):c.3061-1G>A
- Gene:
- ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 13q14.3
- Genomic location:
- Preferred name:
- NM_000053.4(ATP7B):c.3061-1G>A
- HGVS:
- NC_000013.11:g.51944292C>T
- NG_008806.1:g.72203G>A
- NM_000053.4:c.3061-1G>AMANE SELECT
- NM_001005918.3:c.2440-1G>A
- NM_001243182.2:c.2728-1G>A
- NM_001330578.2:c.2827-1G>A
- NM_001330579.2:c.2809-1G>A
- NM_001406511.1:c.3061-1G>A
- NM_001406512.1:c.3061-1G>A
- NM_001406513.1:c.3061-7G>A
- NM_001406514.1:c.3028-1G>A
- NM_001406515.1:c.3007-1G>A
- NM_001406516.1:c.3007-1G>A
- NM_001406517.1:c.2965-1G>A
- NM_001406518.1:c.2965-1G>A
- NM_001406519.1:c.2926-1G>A
- NM_001406520.1:c.2917-1G>A
- NM_001406521.1:c.2917-1G>A
- NM_001406522.1:c.2917-1G>A
- NM_001406523.1:c.3061-1738G>A
- NM_001406524.1:c.2884-1G>A
- NM_001406525.1:c.2866-1G>A
- NM_001406526.1:c.3061-1G>A
- NM_001406527.1:c.2827-1G>A
- NM_001406528.1:c.2827-1G>A
- NM_001406530.1:c.2821-1G>A
- NM_001406531.1:c.2809-1G>A
- NM_001406532.1:c.2809-1G>A
- NM_001406534.1:c.2773-1G>A
- NM_001406535.1:c.2731-1G>A
- NM_001406536.1:c.2731-1G>A
- NM_001406537.1:c.2722-1G>A
- NM_001406538.1:c.2827-1G>A
- NM_001406539.1:c.2632-1G>A
- NM_001406540.1:c.2614-1G>A
- NM_001406541.1:c.2575-1G>A
- NM_001406542.1:c.2575-1G>A
- NM_001406543.1:c.2713-1G>A
- NM_001406544.1:c.2479-1G>A
- NM_001406545.1:c.2413-1G>A
- NM_001406546.1:c.2380-1G>A
- NM_001406547.1:c.2218-1G>A
- NM_001406548.1:c.1771-1G>A
- NC_000013.10:g.52518428C>T
- NM_000053.3:c.3061-1G>A
This HGVS expression did not pass validation- Links:
- dbSNP: rs780955130
- NCBI 1000 Genomes Browser:
- rs780955130
- Molecular consequence:
- NM_001406513.1:c.3061-7G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406523.1:c.3061-1738G>A - intron variant - [Sequence Ontology: SO:0001627]
- NM_000053.4:c.3061-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001005918.3:c.2440-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001243182.2:c.2728-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001330578.2:c.2827-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001330579.2:c.2809-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406511.1:c.3061-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406512.1:c.3061-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406514.1:c.3028-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406515.1:c.3007-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406516.1:c.3007-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406517.1:c.2965-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406518.1:c.2965-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406519.1:c.2926-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406520.1:c.2917-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406521.1:c.2917-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406522.1:c.2917-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406524.1:c.2884-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406525.1:c.2866-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406526.1:c.3061-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406527.1:c.2827-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406528.1:c.2827-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406530.1:c.2821-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406531.1:c.2809-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406532.1:c.2809-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406534.1:c.2773-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406535.1:c.2731-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406536.1:c.2731-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406537.1:c.2722-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406538.1:c.2827-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406539.1:c.2632-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406540.1:c.2614-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406541.1:c.2575-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406542.1:c.2575-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406543.1:c.2713-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406544.1:c.2479-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406545.1:c.2413-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406546.1:c.2380-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406547.1:c.2218-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
- NM_001406548.1:c.1771-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
Condition(s)
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV002234665 | Invitae | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jun 13, 2022) | germline | clinical testing | |
| SCV002819644 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Dec 19, 2022) | germline | clinical testing | |
| SCV004216498 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Sep 5, 2022) | unknown | clinical testing | |
| SCV004847815 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 2, 2023) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Dastsooz H, Dehghani SM, Imanieh MH, Haghighat M, Moini M, Fardaei M.
Gene. 2013 Feb 1;514(1):48-53. doi: 10.1016/j.gene.2012.10.085. Epub 2012 Nov 13.
- PMID:
- 23159873
Splicing in action: assessing disease causing sequence changes.
Baralle D, Baralle M.
J Med Genet. 2005 Oct;42(10):737-48. Review.
- PMID:
- 16199547
- PMCID:
- PMC1735933
Details of each submission
From Invitae, SCV002234665.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (7) |
Description
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 8931691, 22308153, 23159873). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the ATP7B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819644.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
Variant summary: ATP7B c.3061-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246446 control chromosomes (gnomAD). c.3061-1G>A has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Dastsooz_2013, Loudianos_2016). 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. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Baylor Genetics, SCV004216498.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847815.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
The c.3061-1G>A variant in ATP7B has been reported in the homozygous state in 4 individuals and the heterozygous state without a second variant detailed in 3 individuals with Wilson disease (Dastsooz 2013, Loudianos 1996). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3, PVS1_Strong, PM2_Supporting.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: May 7, 2024