ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3402del (p.Ala1135fs) (rs137853281)

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Total submissions: 6
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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 Clinical Services Laboratory,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 2017-08-31 criteria provided, single submitter clinical testing The c.3402delC variant in the ATP7B gene has been reported previously in association with Wilson disease and is the most common variant identified in Venezuelan and Brazilian populations (Tanzi et al., 1993; Deguti et al., 2004; Paradisi et al., 2015). The deletion causes a frameshift starting with codon Alanine 1135, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Ala1135GlnfsX13. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV000169026 SCV000752253 pathogenic Wilson disease 2018-08-27 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. This variant is present in population databases (rs137853281, ExAC 0.02%). This variant has been reported as homozygous or in combination with another ATP7B variant in multiple individuals affected with Wilson disease (PMID: 8298641, 16283883, 25497208, 15024742). ClinVar contains an entry for this variant (Variation ID: 88958). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000523051 SCV000885047 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing The ATP7B c.3402delC; p.Ala1135fs variant (rs137853281), also known as 3400delC or 3403delC, is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease (Deguti 2004, Duc 1998, Firneisz 2002, Margarit 2005, Thomas 1995). The variant is described in the ClinVar database (Variation ID: 88958) and is listed in the Genome Aggregation Database in 0.008% (22/276998) of the population. This variant deletes one nucleotide, causes a frameshift, and is p predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000169026 SCV000189437 not provided Wilson disease no assertion provided not provided

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