Submissions for variant NM_000053.4(ATP7B):c.4058G>A (p.Trp1353Ter)

gnomAD frequency: 0.00001  dbSNP: rs193922110

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029378	SCV000052026	pathogenic	Wilson disease	2021-02-17	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.4058G>A (p.Trp1353X) 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. At-least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 247964 control chromosomes. c.4058G>A has been reported in the literature in at-least one individual affected with Wilson Disease and subsequently cited by others (example, Curtis_1999 and Coffey_2003, Li_2012, Singh_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000029378	SCV000220454	likely pathogenic	Wilson disease	2014-06-25	criteria provided, single submitter	literature only
CeGaT Center for Human Genetics Tuebingen	RCV000415977	SCV000493528	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000415977	SCV000748221	likely pathogenic	not provided	2018-04-04	criteria provided, single submitter	clinical testing	The W1353X variant in the ATP7B gene has been reported previously in association with Wilson disease, however it was identified in a single allele among a cohort of unrelated affected patients without information about zygosity (Curtis et al., 1999). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W1353X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret W1353X as a likely pathogenic variant.
Invitae	RCV000029378	SCV000836786	pathogenic	Wilson disease	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1353*) 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 (rs193922110, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 10502777). ClinVar contains an entry for this variant (Variation ID: 35729). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000029378	SCV001977213	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000029378	SCV004216364	pathogenic	Wilson disease	2023-08-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000415977	SCV004226638	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029378	SCV004563443	pathogenic	Wilson disease	2023-03-03	criteria provided, single submitter	clinical testing	The ATP7B c.4058G>A; p.Trp1353Ter variant (rs193922110) is reported in the literature in individuals affected with Wilson's disease (Coffey 2013, Curtis 1999, Singh 2019). This variant is also reported in ClinVar (Variation ID: 35729), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with Wilson's disease and are considered pathogenic (Coffey 2013, Singh 2019). Based on available information, this variant is considered to be pathogenic. References: Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. PMID: 10502777. Singh N et al. Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. PLoS One. 2019 May 6;14(5):e0215779. PMID: 31059521.