Submissions for variant NM_000053.4(ATP7B):c.3551T>C (p.Ile1184Thr)

gnomAD frequency: 0.00001  dbSNP: rs755817220

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Hadassah Hebrew University Medical Center	RCV001254597	SCV001430587	likely pathogenic	Wilson disease	2019-06-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001254597	SCV001563236	likely pathogenic	Wilson disease	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1184 of the ATP7B protein (p.Ile1184Thr). This variant is present in population databases (rs755817220, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 23518715, 25678388, 32770663). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 977075). 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. 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.
Genome-Nilou Lab	RCV001254597	SCV001977551	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001751521	SCV001985440	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 22692182, 33223529, 36096368, 35220961, 25678388, 34620762, 23518715, 32770663)
Ambry Genetics	RCV002451623	SCV002617780	uncertain significance	Inborn genetic diseases	2014-08-20	criteria provided, single submitter	clinical testing	The p.I1184T variant (also known as c.3551T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3551. The isoleucine at codon 1184 is replaced by threonine, an amino acid with similar properties. In one study, this variant was confirmed to be in cis with a second variant, p.I381S, and in trans with a pathogenic mutation in an individual with a clinical diagnosis of Wilson disease. In another patient in this study, this variant was also seen with p.I381S as well as a different alteration; however phase was not determined (Coffey AJ, et al. Brain 2013 May; 136(Pt 5):1476-87). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6189 samples (12378 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence to date, the clinical significance of the p.I1184T variant remains unclear.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001254597	SCV004805123	likely pathogenic	Wilson disease	2024-03-17	criteria provided, single submitter	research
Natera, Inc.	RCV001254597	SCV002086805	uncertain significance	Wilson disease	2021-07-30	no assertion criteria provided	clinical testing