NM_000053.4(ATP7B):c.3556+1G>T AND Wilson disease
- Germline classification:
- Pathogenic/Likely pathogenic (4 submissions)
- Last evaluated:
- Aug 10, 2022
- 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:
- RCV000587514.7
Allele description [Variation Report for NM_000053.4(ATP7B):c.3556+1G>T]
NM_000053.4(ATP7B):c.3556+1G>T
- 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.3556+1G>T
- HGVS:
- NC_000013.11:g.51941080C>A
- NG_008806.1:g.75415G>T
- NM_000053.4:c.3556+1G>TMANE SELECT
- NM_001005918.3:c.2935+1G>T
- NM_001243182.2:c.3223+1G>T
- NM_001330578.2:c.3322+1G>T
- NM_001330579.2:c.3304+1G>T
- NM_001406511.1:c.3556+1G>T
- NM_001406512.1:c.3556+1G>T
- NM_001406513.1:c.3550+1G>T
- NM_001406514.1:c.3523+1G>T
- NM_001406515.1:c.3502+1G>T
- NM_001406516.1:c.3502+1G>T
- NM_001406517.1:c.3460+1G>T
- NM_001406518.1:c.3460+1G>T
- NM_001406519.1:c.3421+1G>T
- NM_001406520.1:c.3412+1G>T
- NM_001406521.1:c.3412+1G>T
- NM_001406522.1:c.3412+1G>T
- NM_001406523.1:c.3373+1G>T
- NM_001406524.1:c.3379+1G>T
- NM_001406525.1:c.3361+1G>T
- NM_001406526.1:c.3556+1G>T
- NM_001406527.1:c.3322+1G>T
- NM_001406528.1:c.3322+1G>T
- NM_001406530.1:c.3316+1G>T
- NM_001406531.1:c.3304+1G>T
- NM_001406532.1:c.3304+1G>T
- NM_001406534.1:c.3268+1G>T
- NM_001406535.1:c.3226+1G>T
- NM_001406536.1:c.3226+1G>T
- NM_001406537.1:c.3217+1G>T
- NM_001406538.1:c.3178+1306G>T
- NM_001406539.1:c.3127+1G>T
- NM_001406540.1:c.3109+1G>T
- NM_001406541.1:c.3070+1G>T
- NM_001406542.1:c.3070+1G>T
- NM_001406543.1:c.3064+1306G>T
- NM_001406544.1:c.2974+1G>T
- NM_001406545.1:c.2908+1G>T
- NM_001406546.1:c.2875+1G>T
- NM_001406547.1:c.2713+1G>T
- NM_001406548.1:c.2266+1G>T
- NC_000013.10:g.52515216C>A
- NM_000053.2:c.3556+1G>T
- NM_000053.3:c.3556+1G>T
This HGVS expression did not pass validation- Links:
- dbSNP: rs184388696
- NCBI 1000 Genomes Browser:
- rs184388696
- Molecular consequence:
- NM_001406538.1:c.3178+1306G>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_001406543.1:c.3064+1306G>T - intron variant - [Sequence Ontology: SO:0001627]
- NM_000053.4:c.3556+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001005918.3:c.2935+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001243182.2:c.3223+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001330578.2:c.3322+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001330579.2:c.3304+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406511.1:c.3556+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406512.1:c.3556+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406513.1:c.3550+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406514.1:c.3523+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406515.1:c.3502+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406516.1:c.3502+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406517.1:c.3460+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406518.1:c.3460+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406519.1:c.3421+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406520.1:c.3412+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406521.1:c.3412+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406522.1:c.3412+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406523.1:c.3373+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406524.1:c.3379+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406525.1:c.3361+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406526.1:c.3556+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406527.1:c.3322+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406528.1:c.3322+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406530.1:c.3316+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406531.1:c.3304+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406532.1:c.3304+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406534.1:c.3268+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406535.1:c.3226+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406536.1:c.3226+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406537.1:c.3217+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406539.1:c.3127+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406540.1:c.3109+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406541.1:c.3070+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406542.1:c.3070+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406544.1:c.2974+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406545.1:c.2908+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406546.1:c.2875+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406547.1:c.2713+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
- NM_001406548.1:c.2266+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
Condition(s)
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000694450 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Jul 18, 2022) | germline | clinical testing | |
| SCV000791699 | Counsyl | criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) | Likely pathogenic (May 26, 2017) | unknown | clinical testing | |
| SCV002234911 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Aug 10, 2022) | germline | clinical testing | |
| SCV002781785 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Apr 21, 2022) | unknown | 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
ATP7B variant spectrum in a French pediatric Wilson disease cohort.
Couchonnal E, Bouchard S, Sandahl TD, Pagan C, Lion-François L, Guillaud O, Habes D, Debray D, Lamireau T, Broué P, Fabre A, Vanlemmens C, Sobesky R, Gottrand F, Bridoux-Henno L, Belmalih A, Poujois A, Brunet AS, Lachaux A, Bost M.
Eur J Med Genet. 2021 Oct;64(10):104305. doi: 10.1016/j.ejmg.2021.104305. Epub 2021 Aug 13. Erratum in: Eur J Med Genet. 2021 Nov;64(11):104341. doi: 10.1016/j.ejmg.2021.104341. Eur J Med Genet. 2022 Mar;65(3):104453. doi: 10.1016/j.ejmg.2022.104453.
- PMID:
- 34400371
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.
Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RK, Hua Y, Gueroussov S, Najafabadi HS, Hughes TR, Morris Q, Barash Y, Krainer AR, Jojic N, Scherer SW, Blencowe BJ, Frey BJ.
Science. 2015 Jan 9;347(6218):1254806. doi: 10.1126/science.1254806. Epub 2014 Dec 18.
- PMID:
- 25525159
- PMCID:
- PMC4362528
Details of each submission
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694450.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
Variant summary: ATP7B c.3556+1G>T 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: Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249588 control chromosomes (gnomAD). c.3556+1G>T has been reported in the literature in individuals affected with Wilson Disease (Karunas_2000, Khidiyatova_2008 proceedings of World Medical Conference, Balashova_2020, Couchonnal_2021). These data indicate that the variant is likely to be associated with disease. A variant involving the same nucleotide, c.3556+1G>A, has been classififed as likely pathgoenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=1). 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 Counsyl, SCV000791699.1
| # | 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002234911.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
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. ClinVar contains an entry for this variant (Variation ID: 495416). Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 10994503, 26799313, 31708252; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 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 Fulgent Genetics, Fulgent Genetics, SCV002781785.1
| # | 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 | |
Last Updated: Sep 29, 2024