Submissions for variant NM_000053.4(ATP7B):c.3122G>C (p.Arg1041Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003504573	SCV004297244	likely pathogenic	Wilson disease	2023-03-09	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg1041 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10544227, 15024742, 15967699, 18855987, 20931554, 21610751, 22677543, 25982861, 27022412; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with Wilson disease (PMID: 10194254, 10544227). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1041 of the ATP7B protein (p.Arg1041Pro).
All of Us Research Program, National Institutes of Health	RCV003504573	SCV005429691	likely pathogenic	Wilson disease	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 1041 in the N domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 27982432, 34470610, 36872857), including in the homozygous state (PMID: 11405812) and co-occurring with a known pathogenic variant (PMID: 20967755). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1041Trp, is known to be disease-causing (ClinVar Variation ID: 312384). Based on the available evidence, this variant is classified as Likely Pathogenic.