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

gnomAD frequency: 0.00001  dbSNP: rs137853280

Total submissions: 13

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		criteria provided, single submitter	clinical testing
Invitae	RCV000004054	SCV001227124	pathogenic	Wilson disease	2024-01-16	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
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