ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2336G>A (p.Trp779Ter) (rs137853283)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724020 SCV000232469 pathogenic not provided 2014-06-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506812 SCV000602611 pathogenic not specified 2016-12-06 criteria provided, single submitter clinical testing
Invitae RCV000144368 SCV000813134 pathogenic Wilson disease 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp779*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137853283, ExAC 0.02%). This variant has been reported as homozygous or in combination with another ATP7B variant in several individuals affected with Wilson disease (PMID: 8938442, 23982005, Invitae). ClinVar contains an entry for this variant (Variation ID: 156284). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000724020 SCV000890230 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The W779X variant in the ATP7B gene has been reported previously in the homozygous and compound heterozygous state with a second ATP7B variant in multiple individuals with Wilson disease (Waldenstrom et al., 2006; Wiernicka et al., 2017; Kluska et al., 2018). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W779X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret W779X as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000144368 SCV000916619 pathogenic Wilson disease 2017-11-22 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2336G>A (p.Trp779X) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/246088 control chromosomes (gnomAD) at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple compound heterozygote and homozygote WD pts have been reported via publications (Vrabelova_2005, Moller_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000144368 SCV000189435 not provided Wilson disease no assertion provided not provided

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