Submissions for variant NM_000053.4(ATP7B):c.2817G>C (p.Trp939Cys)

dbSNP: rs1057517310

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001916111	SCV002178157	pathogenic	Wilson disease	2024-02-28	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 939 of the ATP7B protein (p.Trp939Cys). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 1409871). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	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.