ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.778dup (p.Gln260fs) (rs786204570)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169312 SCV000220636 likely pathogenic Wilson disease 2014-08-26 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169312 SCV000694470 pathogenic Wilson disease 2017-02-14 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.778dupC (p.Gln260Profs) 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. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. c.813delC (p.Cys271fs), c.845delT (p.Leu282fs), and c.1145_1151delCCCAACT (p.Ser382fs)). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120078 control chromosomes, while it was reported in multiple Wilson disease patients indicating pathogenicity. Moreover, HGMD lists several variants affecting the same codon indicating the variant to be located in a mutational hotspot and further supporting pathogenicity. One clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169312 SCV000752251 pathogenic Wilson disease 2020-04-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln260Profs*10) 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 individuals affected with Wilson disease (PMID: 11216666, 10980554, 19172127, 20082719). This variant is also known as 777insC, 778insC, or 779insC in the literature. ClinVar contains an entry for this variant (Variation ID: 188938). 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 RCV000169312 SCV001470911 pathogenic Wilson disease 2020-08-21 criteria provided, single submitter clinical testing The ATP7B c.778dupC; p.Gln260fs variant (rs786204570) is reported in the literature in several individuals affected with Wilson disease (Manolaki 2009, Merle 2010). This variant is found on a single chromosome in the Genome Aggregation Database (1/248652 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by inserting 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: Manolaki N et al. Wilson disease in children: analysis of 57 cases. J Pediatr Gastroenterol Nutr. 2009;48(1):72-77. Merle U et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 2010;10:8.
GeneDx RCV001560289 SCV001782669 pathogenic not provided 2021-08-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 This variant is associated with the following publications: (PMID: 10980554, 19172127, 11216666, 20082719)
GenomeConnect, ClinGen RCV000169312 SCV000986857 not provided Wilson disease no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 07/25/2018 by GTR ID PerkinElmer Genetics, Inc.. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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