Submissions for variant NM_000053.4(ATP7B):c.3220G>A (p.Ala1074Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003091933	SCV003482227	uncertain significance	Wilson disease	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1074 of the ATP7B protein (p.Ala1074Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. 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. 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.
Baylor Genetics	RCV003091933	SCV005053068	pathogenic	Wilson disease	2024-03-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003091933	SCV005429625	likely pathogenic	Wilson disease	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1074 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). This variant alters a conserved alanine residue in the ATP hydrolysis N domain of the ATP7B protein, a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in two children affected with autosomal recessive Wilson disease, presumed to be compound heterozygous with pathogenic p.Arg778Leu variant in the same gene (PMID: 35222532), as well as in an adult with Wilson disease, presumed to be compound heterozygous with pathogenic p.Thr977Met variant in the same gene (PMID: 30576569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.