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

dbSNP: rs761084829

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668824	SCV000793489	pathogenic	Wilson disease	2017-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000668824	SCV000914630	pathogenic	Wilson disease	2018-08-15	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668824	SCV001370594	pathogenic	Wilson disease	2020-05-01	criteria provided, single submitter	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.
Invitae	RCV000668824	SCV001591097	pathogenic	Wilson disease	2023-06-17	criteria provided, single submitter	clinical testing	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).
Genome-Nilou Lab	RCV000668824	SCV001977387	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
3billion	RCV000668824	SCV002572591	pathogenic	Wilson disease	2022-09-01	criteria provided, single submitter	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.
Baylor Genetics	RCV000668824	SCV004216423	pathogenic	Wilson disease	2023-05-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668824	SCV002087888	pathogenic	Wilson disease	2021-05-12	no assertion criteria provided	clinical testing