Submissions for variant NM_000053.4(ATP7B):c.865C>T (p.Gln289Ter)

gnomAD frequency: 0.00003  dbSNP: rs121907999

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421016	SCV000520886	pathogenic	not provided	2016-12-30	criteria provided, single submitter	clinical testing	The Q289X nonsense variant in the ATP7B gene has been reported to be a common pathogenic variant in the Greek population and has been reported with severe, early-onset Wilson disease (Waldenström et al., 1996; Panagiotakaki et al., 2004; Manolaki et al., 2009; Behari et al., 2010). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000421016	SCV000610993	likely pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000004068	SCV001209439	pathogenic	Wilson disease	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln289*) 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 present in population databases (rs121907999, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 15523622, 15845031, 18403153, 19172127). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3864). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004068	SCV001361696	pathogenic	Wilson disease	2019-07-16	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.865C>T (p.Gln289X) 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 allele was found at a frequency of 2.8e-05 in 248088 control chromosomes (gnomAD). c.865C>T has been reported in the literature in several homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Waldenstrom_1996, Panagiotakaki_2004, Manolaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000421016	SCV001714462	pathogenic	not provided	2019-12-26	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Genome-Nilou Lab	RCV000004068	SCV001977391	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004068	SCV004216309	pathogenic	Wilson disease	2023-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000004068	SCV004563617	pathogenic	Wilson disease	2023-11-27	criteria provided, single submitter	clinical testing	The ATP7B c.865C>T; p.Gln289Ter variant (rs121907999) is reported in the literature in homozygous and compound heterozygous individuals affected with Wilson disease (Couchonnal 2021, Manolaki 2009, Nayagam 2023, Panagiotakaki 2004, Waldenstrom 1996). This variant is also reported in ClinVar (Variation ID: 3864) and is found in the general population with an overall allele frequency of 0.003% (7/248088 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and 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: Couchonnal E et al. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet. 2021 Oct;64(10):104305. PMID: 34400371. Manolaki N et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009 Jan;48(1):72-7. PMID: 19172127. Nayagam JS et al. ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol. 2023 May;21(5):1323-1329.e4. PMID: 36096368. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. PMID: 15523622. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. PMID: 8938442.
OMIM	RCV000004068	SCV000024234	pathogenic	Wilson disease	2005-05-01	no assertion criteria provided	literature only
Counsyl	RCV000004068	SCV000220805	pathogenic	Wilson disease	2017-12-15	no assertion criteria provided	clinical testing