Submissions for variant NM_000053.4(ATP7B):c.3045G>A (p.Leu1015=)

gnomAD frequency: 0.02598  dbSNP: rs1801248

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000145268	SCV000052012	benign	not specified	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3045G>A alters a conserved nucleotide resulting in a synonymous change. At least one computational tool predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.025 in 218250 control chromosomes in the gnomAD database, including 112 homozygotes. The observed variant frequency is approximately 5 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 benign. c.3045G>A has been reported in the literature in individuals affected with Wilson Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease.Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with consensus of benign (benign/likely benign n=7, likely pathogenic n=1, VUS n=1) . Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000145268	SCV000192338	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000145268	SCV000301712	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029365	SCV000384662	benign	Wilson disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000145268	SCV000517725	benign	not specified	2016-02-08	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029365	SCV000602586	benign	Wilson disease	2024-11-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029365	SCV001723341	benign	Wilson disease	2025-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000029365	SCV001750131	benign	Wilson disease	2021-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444441	SCV002753996	benign	Inborn genetic diseases	2016-08-10	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Revvity Omics, Revvity	RCV000029365	SCV003834480	uncertain significance	Wilson disease	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000029365	SCV004361976	benign	Wilson disease	2019-03-28	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000029365	SCV004807209	uncertain significance	Wilson disease	2024-03-26	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000029365	SCV004812752	benign	Wilson disease	2024-01-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000029365	SCV004845427	benign	Wilson disease	2024-10-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000029365	SCV001459709	benign	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
Institute for Genomic Medicine, Nationwide Children's Hospital	RCV000029365	SCV001571615	likely pathogenic	Wilson disease	2021-04-20	flagged submission	research	The c.3045G>A variant is predicted to encode a synonymous change (p.Leu1015Leu) in exon 13 of ATP7B. The prevalence of this variant in the gnomAD database (MAF=0.02544, 126 homozygotes) suggests that it is far too common to cause disease in homozygous state. However, we identified this variant in compound-heterozygous state with a well-established pathogenic truncating variant (p.Arg1319*). Research RNA-seq of proband liver tissue established that the p.Leu1015Leu variant causes exon 13 skipping in approximately 1/3 of transcripts. We propose that this variant is a hypomorphic allele that only causes disease when compound-heterozygous with a loss-of-function variant. We therefore interpret the p.Leu1015Leu variant as likely pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000145268	SCV001807914	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000145268	SCV001922345	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000145268	SCV001926644	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000145268	SCV001955408	benign	not specified		no assertion criteria provided	clinical testing
Mendelics	RCV000029365	SCV002517903	benign	Wilson disease	2023-12-26	flagged submission	clinical testing