Submissions for variant NM_000053.4(ATP7B):c.3556+1G>A

gnomAD frequency: 0.00001  dbSNP: rs184388696

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169452	SCV000694449	pathogenic	Wilson disease	2022-12-31	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3556+1G>A 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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249588 control chromosomes. c.3556+1G>A has been reported in the literature in two unrelated individuals affected with Wilson Disease (Thomas 1995, Ljubic 2016). These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169452	SCV001236884	pathogenic	Wilson disease	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189055). This variant is also known as c.3559+1G>A. Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 26799313; Invitae). This variant is present in population databases (rs184388696, gnomAD 0.006%). This sequence change affects a donor splice site in intron 16 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).
Genome-Nilou Lab	RCV000169452	SCV001977246	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000169452	SCV002060249	pathogenic	Wilson disease	2021-11-11	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.3556+1G>A is a canonical splice variant classified as pathogenic in the context of Wilson disease. c.3556+1G>A has been observed in cases with relevant disease (PMID: 26799313, 7626145). Functional assessments of this variant are not available in the literature. c.3556+1G>A has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, NM_000053.3(ATP7B):c.3556+1G>A is a canonical splice variant that has internal structural support for pathogenicity and 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003159558	SCV003853545	pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Baylor Genetics	RCV000169452	SCV004216336	pathogenic	Wilson disease	2023-09-11	criteria provided, single submitter	clinical testing