ClinVar Miner

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

dbSNP: rs184388696
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587514 SCV000694450 pathogenic Wilson disease 2022-07-18 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3556+1G>T 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: Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249588 control chromosomes (gnomAD). c.3556+1G>T has been reported in the literature in individuals affected with Wilson Disease (Karunas_2000, Khidiyatova_2008 proceedings of World Medical Conference, Balashova_2020, Couchonnal_2021). These data indicate that the variant is likely to be associated with disease. A variant involving the same nucleotide, c.3556+1G>A, has been classififed as likely pathgoenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000587514 SCV000791699 likely pathogenic Wilson disease 2017-05-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000587514 SCV002234911 pathogenic Wilson disease 2022-08-10 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: 495416). Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 10994503, 26799313, 31708252; Invitae). This variant is not present in population databases (gnomAD no frequency). 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).
Fulgent Genetics, Fulgent Genetics RCV000587514 SCV002781785 likely pathogenic Wilson disease 2022-04-21 criteria provided, single submitter clinical testing

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