NM_000053.4(ATP7B):c.3061-12T>A AND Wilson disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Feb 20, 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:
RCV000673212.4

Allele description [Variation Report for NM_000053.4(ATP7B):c.3061-12T>A]

NM_000053.4(ATP7B):c.3061-12T>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.3061-12T>A
HGVS:
  • NC_000013.11:g.51944303A>T
  • NG_008806.1:g.72192T>A
  • NM_000053.4:c.3061-12T>AMANE SELECT
  • NM_001005918.3:c.2440-12T>A
  • NM_001243182.2:c.2728-12T>A
  • NM_001330578.2:c.2827-12T>A
  • NM_001330579.2:c.2809-12T>A
  • NC_000013.10:g.52518439A>T
  • NM_000053.3:c.3061-12T>A
Links:
dbSNP: rs1045194246
NCBI 1000 Genomes Browser:
rs1045194246
Molecular consequence:
  • NM_000053.4:c.3061-12T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001005918.3:c.2440-12T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001243182.2:c.2728-12T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001330578.2:c.2827-12T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001330579.2:c.2809-12T>A - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000798390Counsylcriteria provided, single submitter
Likely pathogenic
(Mar 8, 2018)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001139352Mendelicscriteria provided, single submitter
Pathogenic
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001482032Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 20, 2021)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001590618Invitaecriteria provided, single submitter
Pathogenic
(Sep 21, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis.

Bost M, Piguet-Lacroix G, Parant F, Wilson CM.

J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. doi: 10.1016/j.jtemb.2012.04.024. Epub 2012 Jun 5.

PubMed [citation]
PMID:
22677543

Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain.

Sánchez-Monteagudo A, Álvarez-Sauco M, Sastre I, Martínez-Torres I, Lupo V, Berenguer M, Espinós C.

Clin Genet. 2020 May;97(5):758-763. doi: 10.1111/cge.13719. Epub 2020 Feb 17.

PubMed [citation]
PMID:
32043565
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000798390.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001139352.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482032.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: ATP7B c.3061-12T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site. Two predict the variant weakens a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Loudianos_2002). The variant allele was found at a frequency of 4.1e-06 in 245682 control chromosomes. c.3061-12T>A has been reported in the literature in multiple individuals affected with Wilson Disease (example, Loudianos_2012, Silva_2011, Bost_2012, Dufernez_2013, Sanchez-Monteagudo_2020). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. One submitter has cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Invitae, SCV001590618.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change falls in intron 13 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 12325021, 22687675, 23567103). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557116). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 12325021). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 30, 2021

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