Submissions for variant NM_000053.4(ATP7B):c.2060A>T (p.Asn687Ile)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV002282778	SCV002570337	uncertain significance	Wilson disease	2022-09-02	criteria provided, single submitter	clinical testing	This ATP7B variant (rs778768103) is rare (<0.1%) in a large population dataset (gnomAD: 6/280606 total alleles; 0.0021%; no homozygotes) and has not been reported in ClinVar nor the literature to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while another predicts that it would be tolerated. The asparagine residue at this position is mostly conserved across the vertebrate species assessed, or a similar polar uncharged amino acid is substituted (e.g. glutamine, serine). Bioinformatic analysis predicts that this variant would not affect normal exon 7 splicing, although this has not been confirmed experimentally to our knowledge. This variant is not predicted to occur on the same haplotype as c.1846C>T, but we were not able to confirm whether these variants are on opposite chromosomes. Due to insufficient evidence, we consider the clinical significance of c.2060A>T to be uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002282778	SCV003453335	uncertain significance	Wilson disease	2022-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 687 of the ATP7B protein (p.Asn687Ile). This variant is present in population databases (rs778768103, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. 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. 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.
All of Us Research Program, National Institutes of Health	RCV002282778	SCV004820439	uncertain significance	Wilson disease	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 687 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 6/280606 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.