ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2297C>T (p.Thr766Met) (rs121907997)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780926 SCV000918581 likely pathogenic Wilson disease 2018-02-21 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2297C>T (p.Thr766Met) results in a non-conservative amino acid change located in the transmembrane domain 4 (Dong 2016) of 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 3.6e-05 in 278568 control chromosomes (in gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.2297C>T has been reported in the literature in individuals affected with Wilson Disease (Cox 2005, Mukherjee 2014, Dong 2016). These data indicate that the variant is likely to be associated with disease. Another variant affecting the same nucleotide position, but leading to a different missense change (c.2297C>G (p.Thr766Arg)) is classified as pathogenic in ClinVar and several disease databases, indicating the importance of the affected amino acid residue for protein function. However, to our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.
Invitae RCV000780926 SCV001414069 uncertain significance Wilson disease 2019-06-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 766 of the ATP7B protein (p.Thr766Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121907997, ExAC 0.006%). This variant has been observed in several individuals affected with Wilson disease, but the presence of a second variant was not established in most cases (PMID: 16088907, 29930488, 24094725, 26483271, 27022412, 29321352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr766 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15557537, 21956287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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