Submissions for variant NM_000053.4(ATP7B):c.3863C>T (p.Thr1288Met)

gnomAD frequency: 0.00001  dbSNP: rs373748155

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670692	SCV000795578	uncertain significance	Wilson disease	2017-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779812	SCV000916625	uncertain significance	not specified	2018-05-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3863C>T (p.Thr1288Met) 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 8.1e-06 in 246210 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.1e-06 vs 0.0054), allowing no conclusion about variant significance. c.3863C>T has been reported in the literature in at least 2 individuals affected with Wilson Disease (Lepori_2007, Nicastro_2010). These data indicate that the variant may be associated with disease. 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 VUS-possibly pathogenic.
Genome-Nilou Lab	RCV000670692	SCV002027149	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670692	SCV003442149	likely pathogenic	Wilson disease	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1288 of the ATP7B protein (p.Thr1288Met). This variant is present in population databases (rs373748155, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of ATP7B-related conditions and/or Wilson disease (PMID: 20967755; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554964). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. This variant disrupts the p.Thr1288 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16416207, 17410460; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000670692	SCV005636621	uncertain significance	Wilson disease	2024-03-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000670692	SCV002086791	uncertain significance	Wilson disease	2020-03-13	no assertion criteria provided	clinical testing