Submissions for variant NM_000053.4(ATP7B):c.3402del (p.Ala1135fs)

dbSNP: rs137853281

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169026	SCV000220174	pathogenic	Wilson disease	2014-03-19	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000169026	SCV000384655	pathogenic	Wilson disease	2017-04-27	criteria provided, single submitter	clinical testing	The ATP7B c.3402delC (p.Ala1135GlnfsTer13) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Ala1135GlnfsTer13 variant has been reported in seven studies in which it is found in a total of 80 patients with Wilson disease, including in 24 in a homozygous state, in 48 in a compound heterozygous state and in eight in a heterozygous state (Tanzi et al. 1993; Deguti et al. 2004; Gromadzka et al. 2005; Kucinskas et al. 2008; Machado et al. 2008; Bem et al. 2013; Paradisi et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Ala1135GlnfsTer13 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.
GeneDx	RCV000523051	SCV000617353	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25497208, 31589614, 34400371, 32270360, 32043565, 11690702, 15967699, 23982005, 20082719, 23789284, 8533760, 11857545, 26819605, 12557139, 31708252, 32067425, 8298641, 18855987, 33159804, 15024742)
Invitae	RCV000169026	SCV000752253	pathogenic	Wilson disease	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1135Glnfs*13) 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 (rs137853281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 8298641, 15024742, 16283883, 25497208). ClinVar contains an entry for this variant (Variation ID: 88958). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169026	SCV000885047	pathogenic	Wilson disease	2019-11-25	criteria provided, single submitter	clinical testing	The ATP7B c.3402delC; p.Ala1135fs variant (rs137853281), also published as 3400delC or 3403delC, is reported in the literature in individuals with a clinical diagnosis of Wilson disease (Deguti 2004, Duc 1998, Firneisz 2002, Margarit 2005, Thomas 1995). This variant has been reported in the homozygous state and has also been reported in affected individuals carrying a second pathogenic variant (Deguti 2004). The p.Ala1135fs variant is described in the ClinVar database (Variation ID: 88958) and is observed in the Genome Aggregation Database with a low frequency of 0.01% (17/128568 alleles) in the non-Finnish European population. This variant causes a frameshift by deleting a single nucleotide, so it 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: Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 23(4):398. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 Nov-Dec;6(6):616-23. Firneisz G et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002 Feb 15;108(1):23-8. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7.
CeGaT Center for Human Genetics Tuebingen	RCV000523051	SCV001247793	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PM2, PM3, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169026	SCV001361701	pathogenic	Wilson disease	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3402delC (p.Ala1135GlnfsX13) 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 allele was found at a frequency of 6.4e-05 in 249374 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3402delC has been reported in the literature in multiple individuals affected with Wilson Disease (Balashova_2019, Naorniakowska 2016, Gromadzka 2005, Caca 2001, Tanzi 1993). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated subcellular mislocalization (Huster_2003). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000169026	SCV001368259	pathogenic	Wilson disease	2019-09-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Mayo Clinic Laboratories, Mayo Clinic	RCV000523051	SCV001713637	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169026	SCV001977255	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
3billion	RCV000169026	SCV002572587	pathogenic	Wilson disease	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift 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: VCV000088958 / PMID: 8298641). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000169026	SCV004216275	pathogenic	Wilson disease	2023-10-24	criteria provided, single submitter	clinical testing
OMIM	RCV000169026	SCV000024216	pathogenic	Wilson disease	2020-03-25	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000169026	SCV000189437	not provided	Wilson disease		no assertion provided	not provided
Natera, Inc.	RCV000169026	SCV001455590	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000523051	SCV001807362	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523051	SCV001965063	pathogenic	not provided		no assertion criteria provided	clinical testing