NM_000053.4(ATP7B):c.3556+1G>A AND Wilson disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 10, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000169452.7

Allele description [Variation Report for NM_000053.4(ATP7B):c.3556+1G>A]

NM_000053.4(ATP7B):c.3556+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.3556+1G>A
HGVS:
  • NC_000013.11:g.51941080C>T
  • NG_008806.1:g.75415G>A
  • NM_000053.4:c.3556+1G>AMANE SELECT
  • NM_001005918.3:c.2935+1G>A
  • NM_001243182.2:c.3223+1G>A
  • NM_001330578.2:c.3322+1G>A
  • NM_001330579.2:c.3304+1G>A
  • NC_000013.10:g.52515216C>T
  • NM_000053.2:c.3556+1G>A
  • NM_000053.3:c.3556+1G>A
Links:
dbSNP: rs184388696
NCBI 1000 Genomes Browser:
rs184388696
Molecular consequence:
  • NM_000053.4:c.3556+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001005918.3:c.2935+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001243182.2:c.3223+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001330578.2:c.3322+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001330579.2:c.3304+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Wilson disease (WND)
Synonyms:
Wilson's disease; Hepatolenticular degeneration
Identifiers:
MONDO: MONDO:0010200; MedGen: C0019202; Orphanet: 905; OMIM: 277900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220873Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 11, 2014)
unknownliterature only

PubMed (1)
[See all records that cite this PMID]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000694449Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 1, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001236884Invitaecriteria provided, single submitter
Pathogenic
(Oct 30, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001977246Nilou-Genome Labcriteria provided, single submitter
Pathogenic
(Aug 10, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

ATP7B Gene Mutations in Croatian Patients with Wilson Disease.

Ljubić H, Kalauz M, Telarović S, Ferenci P, Ostojić R, Noli MC, Lepori MB, Hrstić I, Vuković J, Premužić M, Radić D, Ravić KG, Sertić J, Merkler A, Barišić AA, Loudianos G, Vucelić B.

Genet Test Mol Biomarkers. 2016 Mar;20(3):112-7. doi: 10.1089/gtmb.2015.0213. Epub 2016 Jan 22.

PubMed [citation]
PMID:
26799313

The Wilson disease gene: spectrum of mutations and their consequences.

Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW.

Nat Genet. 1995 Feb;9(2):210-7. Erratum in: Nat Genet 1995 Apr;9(4):451.

PubMed [citation]
PMID:
7626145
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000220873.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694449.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: ATP7B c.3556+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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246256 control chromosomes (gnomAD). c.3556+1G>A has been reported in the literature in two unrelated individuals affected with Wilson Disease (Thomas 1995, Ljubic 2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001236884.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in intron 16 of the ATP7B gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs184388696, ExAC 0.01%). This variant has been observed in several individuals affected with Wilson disease (PMID: 26799313, 7626145, Invitae). This variant is also known in the literature as c.3559+1G>A. ClinVar contains an entry for this variant (Variation ID: 189055). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Nilou-Genome Lab, SCV001977246.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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