Submissions for variant NM_000053.4(ATP7B):c.1708-1G>C

gnomAD frequency: 0.00001  dbSNP: rs137853280

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004054	SCV000918604	pathogenic	Wilson disease	2018-07-23	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1708-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant determines exon 5 skipping (Tsai_1999). The variant allele was found at a frequency of 2.9e-05 in 277094 control chromosomes (gnomAD). The variant, c.1708-1G>C, has been reported in the literature in multiple individuals affected with Wilson Disease (Coffey_2013, Hua_2016, Mukherjee_2014, Tsai_1999). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000004054	SCV001163737	pathogenic	Wilson disease	2024-02-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004054	SCV001227124	pathogenic	Wilson disease	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the ATP7B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs137853280, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 9829905, 27398169). This variant is also known as c.1711-1G>C. ClinVar contains an entry for this variant (Variation ID: 3850). 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.
Genome-Nilou Lab	RCV000004054	SCV001977370	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004054	SCV002021384	pathogenic	Wilson disease	2019-03-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000004054	SCV002060193	pathogenic	Wilson disease	2022-01-04	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.1708-1G>C is a canonical splice variant classified as pathogenic in the context of Wilson disease. c.1708-1G>C has been observed in cases with relevant disease (PMID: 24094725, 9829905). Functional assessments of this variant are available in the literature (PMID: 9829905). c.1708-1G>C has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, NM_000053.3(ATP7B):c.1708-1G>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000004054	SCV002807991	pathogenic	Wilson disease	2021-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001579816	SCV004023501	pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Also known as c.1711-1 G>C; This variant is associated with the following publications: (PMID: 35470480, 30655162, 34324271, 35446965, 30275481, 30291343, 9829905, 18034201, 22735241, 23518715, 20931554, 24094725, 11060541, 11405812, 23843956, 21034864, 23275100, 24146181, 7626145, 27398169, 33763395)
CeGaT Center for Human Genetics Tuebingen	RCV001579816	SCV004033265	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PM2, PM3:Supporting, PP4
Neuberg Centre For Genomic Medicine, NCGM	RCV000004054	SCV005073898	pathogenic	Wilson disease	2023-06-22	criteria provided, single submitter	clinical testing	The observed splice acceptor c.1708-1G>C variant in ATP7B gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Wilson disease (WD) (Wang et al., 2023). This variant is reported with the allele frequency of 0.003% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The variant affects AG acceptor splice site in the 3' end of intron 4. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Gromadzka et al., 2005). The spliceAI tool predicts that this splice site variant is damaging. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000004054	SCV005425313	pathogenic	Wilson disease	2024-07-10	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 4 of the ATP7B gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study showed that this variant causes in-frame skipping of exon 5, which contained the final copper-binding site domain (PMID: 9829905). This variant has been observed in many individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 9829905, 10502777, 11043508, 11060541, 11405812, 16133174, 17823867, 18034201, 20417464, 20931554, 21034864, 23518715, 23843956, 24094725, 24146181, 25089800, 27022412, 27982432, 31172689, 32281751, 33640437, 34002136, 34324271, 35444691, 35782615), including in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 9829905, 11043508, 16133174, 20417464, 21034864, 23518715, 23843956, 24094725, 24146181, 31172689). This variant has been identified in 8/280856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000004054	SCV005873589	pathogenic	Wilson disease	2021-12-15	criteria provided, single submitter	clinical testing
OMIM	RCV000004054	SCV000024220	pathogenic	Wilson disease	2000-11-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579816	SCV001808605	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579816	SCV001964003	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004054	SCV002087868	pathogenic	Wilson disease	2020-08-29	no assertion criteria provided	clinical testing