Submissions for variant NM_000053.4(ATP7B):c.3557-6C>T

gnomAD frequency: 0.00314  dbSNP: rs140708492

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000248416	SCV000301719	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029371	SCV000384651	uncertain significance	Wilson disease	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000488125	SCV000527871	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488125	SCV000574958	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ATP7B: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029371	SCV000602595	benign	Wilson disease	2023-11-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029371	SCV000626856	benign	Wilson disease	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000248416	SCV000694451	uncertain significance	not specified	2016-06-28	criteria provided, single submitter	clinical testing	Variant summary: The c.c.3557-6C>T variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that is not widely known to affect splicing, 4/5 splicing prediction tools predict no significant effect on splicing, and Mutation Taster predicts the variant to be a polymorphism. This variant was found in 324/122184 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037672 (250/66362). This subpopulation frequency is lower than the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006), but is high enough to suggest that variant could possibly be a benign polymorphism. Additionally, the variant is regarded as a benign variant in literature (Thomas _1995; Mukherjee_2014) and in at least one database (University of Alberta WD database); however no definite evidence was provided to independently evaluate. There was an internal finding that two variants (c.1922T>C (VUS) and c.2731-2A>G (disease variant)) were identified to co-occur with the variant of interest in a subject undergoing ATP7B gene testing. These variants may explain WD phenotype, albeit phase of the variants would need to be assessed and c.1922T>C has not yet been classified as a disease variant. Taken together, this variant has been classified as a VUS-possibly benign.
Genome-Nilou Lab	RCV000029371	SCV001977549	likely benign	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000029371	SCV004361961	uncertain significance	Wilson disease	2023-01-05	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the -6 position of intron 16 of the ATP7B gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with Wilson disease, however, the authors described this variant as non-disease causing (PMID: 24094725). This variant has been identified in 706/279290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000029371	SCV004822692	uncertain significance	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the -6 position of intron 16 of the ATP7B gene. Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 12 nucleotides upstream of the native intron 16 splice donor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with Wilson disease, however, the authors described this variant as non-disease causing (PMID: 24094725). This variant has been identified in 706/279290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000029371	SCV000733355	likely benign	Wilson disease		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000248416	SCV001808826	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000488125	SCV001931634	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488125	SCV001973879	likely benign	not provided		no assertion criteria provided	clinical testing