GeneBe

rs761084829

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000053.4(ATP7B):​c.994G>T​(p.Glu332*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ATP7B
NM_000053.4 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.41

Publications

11 publications found
Variant links:
Genes affected
ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]
ATP7B Gene-Disease associations (from GenCC):
  • Wilson disease
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-51974226-C-A is Pathogenic according to our data. Variant chr13-51974226-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 553388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP7BNM_000053.4 linkc.994G>T p.Glu332* stop_gained Exon 2 of 21 ENST00000242839.10 NP_000044.2 P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkc.994G>T p.Glu332* stop_gained Exon 2 of 21 1 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
249344
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461870
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727228
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:9
Jun 17, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 553388). 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Wilson disease (PMID: 21219664, 28212618, 30655162). For these reasons, this variant has been classified as Pathogenic. -

Mar 11, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Aug 24, 2017
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 15, 2018
Illumina Laboratory Services, Illumina
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

May 01, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Aug 10, 2021
Genome-Nilou Lab
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 12, 2021
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 02, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Uncertain
0.48
Eigen_PC
Benign
0.21
FATHMM_MKL
Benign
0.60
D
PhyloP100
2.4
Vest4
0.82
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs761084829; hg19: chr13-52548362; API