NM_000053.4(ATP7B):c.994G>T (p.Glu332Ter) AND Wilson disease

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Mar 11, 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:: RCV000668824.20

Allele description [Variation Report for NM_000053.4(ATP7B):c.994G>T (p.Glu332Ter)]

NM_000053.4(ATP7B):c.994G>T (p.Glu332Ter)

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.994G>T (p.Glu332Ter)

HGVS:

NC_000013.11:g.51974226C>A
NG_008806.1:g.42269G>T
NM_000053.4:c.994G>TMANE SELECT
NM_001005918.3:c.994G>T
NM_001243182.2:c.803-142G>T
NM_001330578.2:c.994G>T
NM_001330579.2:c.994G>T
NP_000044.2:p.Glu332Ter
NP_001005918.1:p.Glu332Ter
NP_001317507.1:p.Glu332Ter
NP_001317508.1:p.Glu332Ter
NC_000013.10:g.52548362C>A
NM_000053.3:c.994G>T

Protein change:

E332*

Links:

dbSNP: rs761084829

NCBI 1000 Genomes Browser:

rs761084829

Molecular consequence:

NM_001243182.2:c.803-142G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000053.4:c.994G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001005918.3:c.994G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330578.2:c.994G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330579.2:c.994G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793489	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Aug 24, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28212618, 27982432, 23607698, 23275100, 27022412, 21219664 Citation Link,
SCV000914630	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 15, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21219664, 23275100, 23607698, 27022412, 28212618 Citation Link,
SCV001370594	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 1, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21219664, 27022412, 27982432, 23607698 Citation Link,
SCV001591097	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21219664, 28212618, 30655162, 10441329, 16283883, 28492532
SCV001977387	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]
SCV002087888	Natera, Inc.	no assertion criteria provided	Pathogenic (May 12, 2021)	germline	clinical testing
SCV002572591	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21219664, 25741868
SCV004216423	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 11, 2024)	unknown	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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of one novel and nine recurrent mutations of the ATP7B gene in 11 children with Wilson disease.

Geng J, Wang J, Yao RE, Liu XQ, Fu QH.

World J Pediatr. 2013 May;9(2):158-62. doi: 10.1007/s12519-012-0388-7. Epub 2012 Dec 29.

PubMed [citation]

PMID:: 23275100

Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis.

Dong Y, Ni W, Chen WJ, Wan B, Zhao GX, Shi ZQ, Zhang Y, Wang N, Yu L, Xu JF, Wu ZY.

Theranostics. 2016;6(5):638-49. doi: 10.7150/thno.14596.

PubMed [citation]

PMID:: 27022412
PMCID:: PMC4805659

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000793489.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Illumina Laboratory Services, Illumina, SCV000914630.1

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

Description

The ATP7B c.994G>T (p.Glu332Ter) variant is a stop-gained variant predicted to result in the premature termination of the protein. The p.Glu332Ter variant has been reported in four studies in which it was found in a compound heterozygous state with a missense variant in two individuals diagnosed with Wilson disease (WND) (Geng et al. 2013; Yu et al. 2017) and in at least nine additional affected individuals whose genotype information was not provided and in whom the zygosity of the variant is unknown (Li et al. 2011; Dong et al. 2016). All of the individuals carrying the variant were of Chinese ethnicity. One of the individuals carrying the variant in a compound heterozygous state was diagnosed with the osseomuscular type of WND (Yu et al. 2017). The p.Glu332Ter variant was absent from 100 controls and is not found in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database, in a region of good sequence coverage, so is presumed to be rare. Overexpression followed by immunofluoresence studies of myc-tagged variant protein in both CHO and SH-SY5Y cells, demonstrated that the variant resulted in a mislocalisation, showing a diffuse and homogenous distribution in the cytosol, compared to the wild type protein shown to be located in the Golgi apparatus (Zhu et al. 2013). Based on the collective evidence and potential impact of stop-gained variants, the p.Glu332Ter variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370594.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ATP7B c.994G>T (p.Glu332X) 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 249344 control chromosomes. c.994G>T has been reported in the literature in multiple individuals affected with Wilson Disease (examples: Li_2011, Dong_2016, Cheng_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant results in mislocalization of the ATP7B protein in-vitro (Zhu_2013). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001591097.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553388). This premature translational stop signal has been observed in individual(s) with clinical features of Wilson disease (PMID: 21219664, 28212618, 30655162). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu332*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883).

#	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, SCV001977387.1

#	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 Natera, Inc., SCV002087888.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002572591.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. The stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000553388 / PMID: 21219664). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004216423.2

#	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

Last Updated: Sep 29, 2024

Relating variation to medicine