Submissions for variant NM_000053.4(ATP7B):c.3843dup (p.Val1282fs)

dbSNP: rs1957043255

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001231852	SCV001404387	pathogenic	Wilson disease	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1282Cysfs*22) 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 Wilson disease (PMID: 27398169). ClinVar contains an entry for this variant (Variation ID: 958649). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001231852	SCV001977230	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001231852	SCV002049143	pathogenic	Wilson disease	2021-11-26	criteria provided, single submitter	clinical testing	The ATP7B c.3843dupT; p.Val1282CysfsTer22 variant is reported in the literature in individuals with Wilson disease, including in at least one individual with an additional pathogenic variant (Hua 2016, Li 2011). The variant is reported in the ClinVar database (Variation ID: 958649) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss of function is the pathogenic mechanism for Wilson disease and other frameshift variants in this region have been described in affected individuals and are considered pathogenic (Gromadzka 2005). Based on available information, the c.3843dupT; p.Val1282CysfsTer22 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. PMID: 16283883. Hua R et al Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. PMID: 27398169. Li XH et al. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. BMC Med Genet. 2011 Jan 11;12:6. PMID: 21219664.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001231852	SCV002570697	pathogenic	Wilson disease	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3843dupT (p.Val1282CysfsX22) 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 251274 control chromosomes (gnomAD and publication data). c.3843dupT has been reported in the literature in individuals affected with Wilson Disease (Merle_2010, Li_2011, Hua_2016, Xiao_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001231852	SCV002811668	pathogenic	Wilson disease	2022-02-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003222267	SCV003917288	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PM2, PM3, PS4:Moderate
Baylor Genetics	RCV001231852	SCV004216328	pathogenic	Wilson disease	2023-09-18	criteria provided, single submitter	clinical testing