Submissions for variant NM_000053.4(ATP7B):c.2668G>A (p.Val890Met)

gnomAD frequency: 0.00003  dbSNP: rs786204718

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169535	SCV000221015	likely pathogenic	Wilson disease	2015-01-08	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514615	SCV000609693	pathogenic	not provided	2017-08-23	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000169535	SCV000845443	pathogenic	Wilson disease	2024-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169535	SCV000916634	pathogenic	Wilson disease	2018-11-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2668G>A (p.Val890Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277226 control chromosomes. c.2668G>A has been reported in the literature in multiple individuals affected with Wilson Disease. 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169535	SCV001228417	pathogenic	Wilson disease	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 890 of the ATP7B protein (p.Val890Met). This variant is present in population databases (rs786204718, gnomAD 0.004%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11216666, 14986826, 22308153, 22484412, 22677543, 23235335, 27022412, 29637721, 29979436; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169535	SCV001810286	likely pathogenic	Wilson disease	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169535	SCV004216415	pathogenic	Wilson disease	2024-03-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000169535	SCV004845490	pathogenic	Wilson disease	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 890 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with Wilson disease (PMID: 11216666, 14986826, 20517649, 22308153, 20958917, 22484412, 22677543, 23235335, 23486543, 27022412, 28753182, 27982432, 29637721, 30230192, 33879678, 34240825, 34002136, 34400371). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 30230192, 33879678, 34002136) and homozygous state (PMID: 34400371). This variant has been identified in 5/280992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000514615	SCV005090088	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169535	SCV002087840	pathogenic	Wilson disease	2020-04-27	no assertion criteria provided	clinical testing