Submissions for variant NM_000053.4(ATP7B):c.1520_1523del (p.Glu507fs)

dbSNP: rs772000260

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280593	SCV001467802	pathogenic	Wilson disease	2020-12-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1520_1523delAAAG (p.Glu507GlyfsX16) 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. The variant allele was found at a frequency of 4e-06 in 249080 control chromosomes (gnomAD). c.1520_1523delAAAG has been reported in the literature in individuals (in both homozygous and compound heterozygous state) affected with Wilson Disease (example: Coffey_2013, Czlonkowska_2018, Dziezyc_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001280593	SCV001587416	pathogenic	Wilson disease	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu507Glyfs*16) 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 (rs772000260, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 10502777, 16283883). This variant is also known as 1518delAGAA. ClinVar contains an entry for this variant (Variation ID: 992220). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001280593	SCV004216476	pathogenic	Wilson disease	2023-11-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001280593	SCV004848407	likely pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Glu507GlyfsX16 variant in ATP7B has been reported in at least 1 individual with Wilson disease, but a second variant was not reported (Curtis 1999 PMID 10502777). This variant is has been identified in 0.0008% (1/112804) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 507 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PVS1, PM2.
Natera, Inc.	RCV001280593	SCV002087873	pathogenic	Wilson disease	2020-05-25	no assertion criteria provided	clinical testing