NM_000053.4(ATP7B):c.4150dup (p.Tyr1384fs) AND Wilson disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000668906.4

Allele description [Variation Report for NM_000053.4(ATP7B):c.4150dup (p.Tyr1384fs)]

NM_000053.4(ATP7B):c.4150dup (p.Tyr1384fs)

Gene:

ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_000053.4(ATP7B):c.4150dup (p.Tyr1384fs)

HGVS:

NC_000013.11:g.51935004dup
NG_008806.1:g.81491dup
NM_000053.4:c.4150dupMANE SELECT
NM_001005918.3:c.3529dup
NM_001243182.2:c.3817dup
NM_001330578.2:c.3916dup
NM_001330579.2:c.3898dup
NP_000044.2:p.Tyr1384fs
NP_001005918.1:p.Tyr1177fs
NP_001230111.1:p.Tyr1273fs
NP_001317507.1:p.Tyr1306fs
NP_001317508.1:p.Tyr1300fs
NC_000013.10:g.52509139_52509140insA
NC_000013.10:g.52509140dup
NM_000053.3:c.4150dupT

Protein change:

Y1177fs

Links:

dbSNP: rs1555282316

NCBI 1000 Genomes Browser:

rs1555282316

Molecular consequence:

NM_000053.4:c.4150dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001005918.3:c.3529dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001243182.2:c.3817dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330578.2:c.3916dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330579.2:c.3898dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793581	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Aug 21, 2017)	unknown	clinical testing	Citation Link,
SCV001983620	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 23, 2021)	germline	clinical testing	Citation Link,
SCV004216412	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 31, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004373182	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26799313, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000793581.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983620.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: ATP7B c.4150dupT (p.Tyr1384LeufsX2) 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. The variant was absent in 247262 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4150dupT in individuals affected with Wilson Disease and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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, SCV004216412.1

#	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 Invitae, SCV004373182.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Tyr1384Leufs*2) in the ATP7B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the ATP7B protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 553449). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ATP7B protein in which other variant(s) (p.Arg1459Glyfs*2) have been determined to be pathogenic (PMID: 26799313). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been 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

Last Updated: Feb 28, 2024

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