Submissions for variant NM_000053.4(ATP7B):c.254G>C (p.Gly85Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003119308	SCV003790628	likely pathogenic	Wilson disease	2022-09-01	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. 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.Gly85 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17919502, 19937698, 22240481, 30702195, 32043565). 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 expected to disrupt ATP7B protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 85 of the ATP7B protein (p.Gly85Ala).
Neuberg Centre For Genomic Medicine, NCGM	RCV003119308	SCV004176666	uncertain significance	Wilson disease	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.254G>C (p.Gly85Ala) variant in ATP7B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gly85Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Gly85Ala in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 85 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV003119308	SCV004834932	uncertain significance	Wilson disease	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 85 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATP7B-related disorders in the literature. 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.Gly85Val, is known to cause disease (ClinVar variation ID: 189037), indicating that glycine at this position is important for ATP7B protein function. Due to the insufficient variant-specific clinical and functional data, the role of p.Gly85Ala variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.