Submissions for variant NM_000053.4(ATP7B):c.3889G>A (p.Val1297Ile)

gnomAD frequency: 0.00192  dbSNP: rs148399850

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078053	SCV000109891	benign	not specified	2013-11-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078053	SCV000192353	benign	not specified	2019-02-01	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490530	SCV000267217	uncertain significance	Wilson disease	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000078053	SCV000520883	likely benign	not specified	2017-12-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490530	SCV000752282	benign	Wilson disease	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000490530	SCV000883436	likely benign	Wilson disease	2023-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078053	SCV000918600	benign	not specified	2018-06-21	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3889G>A (p.Val1297Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 279784 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3889G>A has been reported as a "polymorphism" in the literature in individuals affected with Wilson Disease. Multiple studies reported not significantly different MAF of variant in diesease vs control cohort (Dong_2016 and Hua_2016) and listed variant as polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation (2 benign, 2 likely benign and 1 VUS). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000490530	SCV001139347	benign	Wilson disease	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490530	SCV001268482	likely benign	Wilson disease	2018-09-17	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genome-Nilou Lab	RCV000490530	SCV001716353	benign	Wilson disease	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354273	SCV002623542	likely benign	Inborn genetic diseases	2014-10-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV003333954	SCV004042566	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ATP7B: BS1, BS2
Color Diagnostics, LLC DBA Color Health	RCV000490530	SCV004361956	likely benign	Wilson disease	2022-09-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000490530	SCV004844578	likely benign	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000490530	SCV001466731	benign	Wilson disease	2020-04-03	no assertion criteria provided	clinical testing