ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.4039G>A (p.Gly1347Ser)

gnomAD frequency: 0.00006  dbSNP: rs587783318
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000145281 SCV000192358 likely pathogenic Wilson disease 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000145281 SCV001221182 pathogenic Wilson disease 2021-12-15 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1347 of the ATP7B protein (p.Gly1347Ser). This variant is present in population databases (rs587783318, gnomAD 0.08%). This missense change has been observed in individual(s) with Wilson disease (PMID: 24555712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157956). 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 expected to disrupt ATP7B protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260437 SCV001437434 uncertain significance not specified 2020-09-21 criteria provided, single submitter clinical testing Variant summary: ATP7B c.4039G>A (p.Gly1347Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 243552 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00012 vs 0.0054), allowing no conclusion about variant significance. c.4039G>A has been reported in the literature in at least two family members affected with Wilson Disease (Forbes_2014). The variant segregated with disease in this family. These data indicate that the variant may be associated with disease, however additional studies are needed to confirm these findings. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, until additional information become available, the variant was classified as VUS-possibly pathogenic.
Genome-Nilou Lab RCV000145281 SCV001977531 uncertain significance Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Natera, Inc. RCV000145281 SCV001455573 uncertain significance Wilson disease 2020-09-16 no assertion criteria provided clinical testing

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