Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001916111 | SCV002178157 | pathogenic | Wilson disease | 2021-08-08 | criteria provided, single submitter | clinical testing | 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. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with Wilson disease (PMID: 23430908). It has also been observed to segregate with disease in related individuals. This sequence change replaces tryptophan with cysteine at codon 939 of the ATP7B protein (p.Trp939Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). |
| All of Us Research Program, |
RCV001916111 | SCV004825130 | likely pathogenic | Wilson disease | 2023-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces tryptophan with cysteine at codon 939 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). Although functional studies have not been reported for this variant, it alters a conserved tryptophan residue in the transmembrane domain M5 of the ATP7B protein (a.a. 918 - 946), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). The p.Trp939Cys variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 17272994, 23430908, 30655162), including at least one individual in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 17272994) and in multiple individuals in the homozygous state (PMID: 23430908). A different DNA substitution with the same protein consequence (c.2817G>T p.Trp939Cys) has also been identified in patients with autosomal recessive Wilson disease (ClinVar variation ID: 371483). 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. |