ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3140A>T (p.Asp1047Val)

gnomAD frequency: 0.00001  dbSNP: rs1395504465
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001389302 SCV001590616 pathogenic Wilson disease 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1047 of the ATP7B protein (p.Asp1047Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 23843956, 27022412, 27398169, 30384382). ClinVar contains an entry for this variant (Variation ID: 1075644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001508711 SCV001715046 likely pathogenic not provided 2019-07-23 criteria provided, single submitter clinical testing PS4_moderate, PM2, PM3, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001389302 SCV001748743 pathogenic Wilson disease 2023-05-26 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3140A>T (p.Asp1047Val) results in a non-conservative amino acid change located in the ATP loop domain (Dong_2016) and P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249210 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3140A>T has been widely reported in the literature among both homozygous and compound heterozygous, phenotypically well-characterized Chinese individuals affected with classic features of Wilson Disease (e.g., Mak_2008, Gu_2013, Dong_2016, Hua_2016, Xiao_2019, Zhang_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27022412, 23843956, 27398169, 18760268, 30384382, 35220961). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV001389302 SCV001977273 likely pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001508711 SCV004033260 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing ATP7B: PM3:Very Strong, PM2
Baylor Genetics RCV001389302 SCV004216376 pathogenic Wilson disease 2023-07-20 criteria provided, single submitter clinical testing

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