ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1145_1151del (p.Ser382fs) (rs1176709391)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627424 SCV000748422 likely pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing The c.1145_1151delCCCAACT variant in the ATP7B gene has been reported previously in association with Wilson disease (Curtis et al., 1999). This variant causes a frameshift starting with codon Serine 382, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Ser382TrpfsX24. The c.1145_1151delCCCAACT variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1145_1151delCCCAACT as a likely pathogenic variant.
Invitae RCV000631236 SCV000752256 pathogenic Wilson disease 2020-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser382Trpfs*24) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Wilson disease (PMID: 10502777). This variant is also known as 1143del7 in the literature. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000631236 SCV000918597 pathogenic Wilson disease 2018-05-29 criteria provided, single submitter clinical testing Variant summary: ATP7B c.1145_1151delCCCAACT (p.Ser382TrpfsX24) 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 (eg. c.1531C>T (p.Gln511X), c.1716delG (p.Met573X), and c.1745_1746delTA (p.Ile582fsX25)). The variant allele was found at a frequency of 1.4e-05 in 277184 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (1.4e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.1145_1151delCCCAACT, has been reported in the literature in multiple individuals affected with Wilson Disease (Curtis_1999, Coffey_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as "pathogenic/likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000631236 SCV001163739 pathogenic Wilson disease criteria provided, single submitter clinical testing

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