NM_000053.4(ATP7B):c.3472_3482del (p.Gly1158fs) AND Wilson disease

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 15, 2023
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:: RCV001293508.14

Allele description [Variation Report for NM_000053.4(ATP7B):c.3472_3482del (p.Gly1158fs)]

NM_000053.4(ATP7B):c.3472_3482del (p.Gly1158fs)

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.3472_3482del (p.Gly1158fs)

HGVS:

NC_000013.11:g.51941155_51941165del
NG_008806.1:g.75330_75340del
NM_000053.4:c.3472_3482delMANE SELECT
NM_001005918.3:c.2851_2861del
NM_001243182.2:c.3139_3149del
NM_001330578.2:c.3238_3248del
NM_001330579.2:c.3220_3230del
NP_000044.2:p.Gly1158fs
NP_001005918.1:p.Gly951fs
NP_001230111.1:p.Gly1047fs
NP_001317507.1:p.Gly1080fs
NP_001317508.1:p.Gly1074fs
NC_000013.10:g.52515291_52515301del
NC_000013.10:g.52515291_52515301delATGGTTAAACC
NM_000053.3:c.3472_3482del11

Protein change:

G1047fs

Links:

dbSNP: rs1566461818

NCBI 1000 Genomes Browser:

rs1566461818

Molecular consequence:

NM_000053.4:c.3472_3482del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001005918.3:c.2851_2861del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001243182.2:c.3139_3149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330578.2:c.3238_3248del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330579.2:c.3220_3230del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV001482095	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9311736, 18855987, 27992490, 23885147, 31942415 Citation Link,
SCV001977252	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002047962	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Nov 17, 2020)	germline	clinical testing	Citation Link,
SCV004216358	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004828837	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses.

Shah AB, Chernov I, Zhang HT, Ross BM, Das K, Lutsenko S, Parano E, Pavone L, Evgrafov O, Ivanova-Smolenskaya IA, Annerén G, Westermark K, Urrutia FH, Penchaszadeh GK, Sternlieb I, Scheinberg IH, Gilliam TC, Petrukhin K.

Am J Hum Genet. 1997 Aug;61(2):317-28.

PubMed [citation]

PMID:: 9311736
PMCID:: PMC1715895

High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson's disease.

Kucinskas L, Jeroch J, Vitkauskiene A, Sakalauskas R, Petrenkiene V, Kucinskas V, Naginiene R, Schmidt H, Kupcinskas L.

World J Gastroenterol. 2008 Oct 14;14(38):5876-9.

PubMed [citation]

PMID:: 18855987
PMCID:: PMC2751898

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001482095.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: ATP7B c.3472_3482del11 (p.Gly1158PhefsX2) 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 allele was found at a frequency of 4e-06 in 249588 control chromosomes (gnomAD). c.3472_3482del11 has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Shah_1997, Kucinskas_2008, Wiernicka_2013, Todorov_2016, Zarina_2019). These data indicate that the variant is very likely to be associated with disease. No 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 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 Genome-Nilou Lab, SCV001977252.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002047962.1

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

Description

The ATP7B c.3472_3482del; p.Gly1158PhefsTer2 variant (rs1566461818) is reported in the literature in several individuals affected with Wilson disease (Gromadzka 2005, Shah 1997, Zarina 2017). At least one affected proband with this variant also carried a second pathogenic variant (Zarina 2017). The c.3472_3482del variant is found on a single chromosome in the Genome Aggregation Database (1/249588 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 11 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Gromadzka G et al. 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. Clin Genet. 2005 Dec;68(6):524-32. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. Zarina A et al. Genetic variation spectrum in ATP7B gene identified in Latvian patients with Wilson disease. Mol Genet Genomic Med. 2017 Jun 7;5(4):405-409.

#	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, SCV004216358.1

#	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 All of Us Research Program, National Institutes of Health, SCV004828837.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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