Submissions for variant NM_000053.4(ATP7B):c.2810del (p.Val937fs)

dbSNP: rs1057516643

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409795	SCV000485998	likely pathogenic	Wilson disease	2016-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000482624	SCV000568296	pathogenic	not provided	2016-12-20	criteria provided, single submitter	clinical testing	The c.2810delT variant in the ATP7B gene has been reported previously in patients with Wilson disease (Wu et al. 2001; Wan et al. 2010). Expression studies found that c.2810delT completely inhibited copper-transporting activity of the ATP7B protein (Wan et al., 2010). The c.2810delT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2810delT deletion causes a frameshift starting with codon Valine 937, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Val937GlyfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.2810delT to be a pathogenic variant.
Invitae	RCV000409795	SCV000962320	pathogenic	Wilson disease	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val937Glyfs*5) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 20931554, 26483271; Invitae). ClinVar contains an entry for this variant (Variation ID: 370632). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409795	SCV001339143	pathogenic	Wilson disease	2020-03-16	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2810delT (p.Val937GlyfsX5) 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. The variant allele was found at a frequency of 4e-06 in 249570 control chromosomes (gnomAD). c.2810delT has been reported in the literature in individuals (homozygous and compound heterozygous) affected with Wilson Disease (e.g. Wan_2010, Hui_2013, Mak_2008). These data indicate that the variant is likely to be associated with disease. In copper resistance assay to determine the effect of the mutation on cell survival, the variant completely inhibited copper-transporting activity as indicated by the rapid death of cells expressing the mutant ATP7B when they were exposed to 20uM copper (Wan_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000409795	SCV001977302	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000482624	SCV002525820	pathogenic	not provided	2021-04-13	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2
Ambry Genetics	RCV002436230	SCV002749246	pathogenic	Inborn genetic diseases	2015-11-24	criteria provided, single submitter	clinical testing	The c.2810delT pathogenic mutation, located in coding exon 12 of the ATP7B gene, results from a deletion of one nucleotide at nucleotide position 2810, causing a translational frameshift with a predicted alternate stop codon. This mutation has been detected in chromosomes from multiple individuals with Wilson disease (Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5, Mak CM, et al. J. Hum. Genet. 2008;53(1):55-63, Wu ZY, et al. Arch. Neurol. 2001; 58(6):971-6, Cox DW, et al. Hum. Mutat. 2005;26(3):280). In addition, this alteration was detected in the homozygous state in an individual with significant reduction of Wilson disease symptoms. The authors of this functional study showed that this mutation is unable to produce functional ATP7B protein and completely inhibits copper-transporting activity. However, this alteration also results in the expression of alternative in frame splice variants that retain copper transporting activity at a significantly higher level than wild type protein, which, authors propose, are responsible for this individuals attenuated phenotype (Wan L, et al. Hepatology 2010;52(5):1662-70). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Baylor Genetics	RCV000409795	SCV004216481	pathogenic	Wilson disease	2023-01-12	criteria provided, single submitter	clinical testing