NM_000053.4(ATP7B):c.2227del (p.Tyr743fs) AND Wilson disease

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 24, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001070456.2

Allele description [Variation Report for NM_000053.4(ATP7B):c.2227del (p.Tyr743fs)]

NM_000053.4(ATP7B):c.2227del (p.Tyr743fs)

Gene:
ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q14.3
Genomic location:
Preferred name:
NM_000053.4(ATP7B):c.2227del (p.Tyr743fs)
HGVS:
  • NC_000013.11:g.51958441del
  • NG_008806.1:g.58056del
  • NM_000053.4:c.2227delMANE SELECT
  • NM_001005918.3:c.1870-832del
  • NM_001243182.1:c.1894del
  • NM_001330578.1:c.2122-832del
  • NM_001330579.2:c.1975del
  • NP_000044.2:p.Tyr743fs
  • NP_001230111.1:p.Tyr632fs
  • NP_001317508.1:p.Tyr659fs
  • NC_000013.10:g.52532575del
  • NC_000013.10:g.52532577del
  • NM_000053.3:c.2227del
  • NM_000053.3:c.2227delT
  • p.Tyr743Ilefs*19
Protein change:
Y632fs
Links:
Molecular consequence:
  • NM_000053.4:c.2227del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001243182.1:c.1894del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001330579.2:c.1975del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001005918.3:c.1870-832del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001330578.1:c.2122-832del - 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
SCV001235688Invitaecriteria provided, single submitter
Pathogenic
(Dec 20, 2019)
germlineclinical testing

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

SCV001431917Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Aug 24, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.

Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC.

Hum Mol Genet. 1999 Sep;8(9):1665-71.

PubMed [citation]
PMID:
10441329

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, Schmidt HH, Genschel J, Bochow B, Rodo M, Tarnacka B, Litwin T, Chabik G, Członkowska A.

Clin Genet. 2005 Dec;68(6):524-32.

PubMed [citation]
PMID:
16283883
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001235688.2

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

Description

This sequence change creates a premature translational stop signal (p.Tyr743Ilefs*19) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 23551039). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001431917.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: ATP7B c.2227delT (p.Tyr743IlefsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 249582 control chromosomes (gnomAD). c.2227delT has been reported in the literature in one individual affected with Wilson Disease (Aggarwal_2013). The 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. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. 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

Last Updated: Jun 14, 2021

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