Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000665305 | SCV000789401 | likely pathogenic | Wilson disease | 2017-02-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000665305 | SCV002297457 | likely pathogenic | Wilson disease | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1043 of the ATP7B protein (p.Leu1043Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP7B-related conditions and/or Wilson disease (PMID: 8931691, 23486543, 23518715, 24798599, 25982861, 36096368). This variant is also known as Leu1044Pro. ClinVar contains an entry for this variant (Variation ID: 550536). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV000665305 | SCV004216332 | likely pathogenic | Wilson disease | 2023-09-15 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV003480751 | SCV004226657 | likely pathogenic | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing | PP3, PP4, PM2, PM3, PS3_moderate, PS4_moderate |
| ARUP Laboratories, |
RCV000665305 | SCV004564301 | likely pathogenic | Wilson disease | 2022-12-30 | criteria provided, single submitter | clinical testing | The ATP7B c.3128T>C; p.Leu1043Pro variant (rs1412025509) is reported in the literature in multiple individuals affected with Wilson disease, including several individuals that were homozygous or carried a second disease-causing variant (Curtis 1999, Guggilla 2015, Loudianos 1999, Nayagam 2022). The p.Leu1043Pro variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 1043 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.821). Consistent with these predictions, functional assays suggest the variant protein has reduced function, as it failed to complement growth on iron-limited media similar to wildtype ATP7B in a heterologous yeast assay (Luoma 2010). Based on available information, this variant is considered to be likely pathogenic. References: Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. PMID: 10502777. Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. PMID: 25982861. Loudianos G et al. Molecular characterization of wilson disease in the Sardinian population--evidence of a founder effect. Hum Mutat. 1999;14(4):294-303. PMID: 10502776. Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 May;31(5):569-77. PMID: 20333758. Nayagam JS et al. ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol. 2022 Sep 9:S1542-3565(22)00837-0. PMID: 36096368. |