Submissions for variant NM_000053.4(ATP7B):c.3451C>T (p.Arg1151Cys)

gnomAD frequency: 0.00004  dbSNP: rs755554442

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169188	SCV000220432	likely pathogenic	Wilson disease	2014-06-20	criteria provided, single submitter	literature only
Hadassah Hebrew University Medical Center	RCV000169188	SCV001572883	likely pathogenic	Wilson disease	2019-06-20	criteria provided, single submitter	clinical testing
Invitae	RCV000169188	SCV001575131	pathogenic	Wilson disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1151 of the ATP7B protein (p.Arg1151Cys). This variant is present in population databases (rs755554442, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 21645214, 23333878, 27398169). ClinVar contains an entry for this variant (Variation ID: 188839). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 21645214). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10544227, 15205462, 30655162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169188	SCV001752787	likely pathogenic	Wilson disease	2022-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001596981	SCV001830740	likely pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Lee et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24253677, 22692182, 17949296, 26215059, 22484412, 21645214, 23333878, 32231684, 30275481, 23089210, 15147237, 27022412, 23235335, 34470610, 34620762, Rosa[article]2021)
Mayo Clinic Laboratories, Mayo Clinic	RCV001596981	SCV002525814	likely pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169188	SCV002765106	pathogenic	Wilson disease	2022-12-06	criteria provided, single submitter	clinical testing	This variant was identified with NM_000053.4:c.1285+5G>T, phase is unknown. Both variants were reported as secondary findings in a patient without Wilson associated symptoms Criteria applied: PM3_STR, PS3_MOD, PM5, PM2_SUP, PP3
Revvity Omics, Revvity	RCV000169188	SCV003823278	likely pathogenic	Wilson disease	2021-11-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169188	SCV003835991	pathogenic	Wilson disease	2022-12-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003422061	SCV004117976	likely pathogenic	ATP7B-related condition	2023-10-11	criteria provided, single submitter	clinical testing	The ATP7B c.3451C>T variant is predicted to result in the amino acid substitution p.Arg1151Cys. This variant was reported in multiple individuals with Wilson disease (Lepori et al. 2007. PubMed ID: 17949296, Lee et al. 2011. PubMed ID: 21645214, Hua et al. 2016. PubMed ID: 27398169). It is unclear based on the literature if these variants were seen in the homozygous or compound heterozygous state. However, it was reported with a second pathogenic variant in one patient with clinical and biochemical features consistent with Wilson disease (Simsek Papur et al. 2013. PubMed ID: 23333878). In vitro functional characterization suggests that this variant is deleterious (Lee et al. 2011. PubMed ID: 21645214). Of note, two additional missense variants affecting this residue have been reported in association with Wilson disease with unclear evidence of pathogenicity (p.Arg1151His and p.Arg1151Gly; Morgan et al. 2004. PubMed ID: 15205462, Loudianos et al. 1999. PubMed ID: 10544227, Dong et al. 2016. PubMed ID: 27022412). This variant is located in exon 16, where a large number of ATP7B variants have been associated with disease (Li. 2021. PubMed ID: 34470610). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52515322-G-A). Of note, this variant was also detected in a patient who carried two additional likely pathogenic/pathogenic variants in this gene. Overall, the collective evidence suggests that this variant is likely pathogenic.
GenomeConnect, ClinGen	RCV000169188	SCV002075006	not provided	Wilson disease		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 04-18-2019 by Lab or GTR ID 507240. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000169188	SCV002086810	likely pathogenic	Wilson disease	2020-03-23	no assertion criteria provided	clinical testing