Submissions for variant NM_000053.4(ATP7B):c.3121C>T (p.Arg1041Trp) (rs746485916)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000308454	SCV000384660	likely pathogenic	Wilson disease	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ATP7B c.3121C>T (p.Arg1041Trp) missense variant has been identified in a compound heterozygous state in four patients with Wilson disease, including two siblings (Loudianos et al. 1998; Loudianos et al. 1999; Deguti et al. 2004; Kucinskas et al. 2008). Simsek Papur et al. (2013) and Guggilla et al. (2015) also identified the p.Arg1041Trp variant in four alleles in a cohort of affected individuals where zygosity was not stated. Coffey et al. (2013) reported the p.Arg1041Trp variant in a heterozygous state in one of 5,162 controls and it is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Experiments in yeast revealed that the p.Arg1041Trp variant was able to complement copper transport function, however the evidence is limited as other aspects of protein function were not evaluated (Hsi et al. 2008). Based on the available evidence, the p.Arg1041Trp variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000308454	SCV000752254	pathogenic	Wilson disease	2020-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1041 of the ATP7B protein (p.Arg1041Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs746485916, ExAC 0.008%). This variant has been reported in numerous individuals affected with Wilson disease who were homozygous or compound heterozygous with a second ATP7B pathogenic variant (PMID: 25982861, 15024742, 18855987, 10544227, 21610751, 20931554, 22677543, 27022412, 15967699, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 312384). Experimental studies have shown that this missense change behaves as wild-type in yeast-based functional complementation assays (PMID: 18203200). However, the clinical significance of this finding is unclear. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg1041 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 10194254), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000308454	SCV000790626	likely pathogenic	Wilson disease	2017-03-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000308454	SCV001455595	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing