Submissions for variant NM_000053.4(ATP7B):c.1168A>G (p.Ile390Val)

gnomAD frequency: 0.00001  dbSNP: rs770903362

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174860	SCV001338250	uncertain significance	not specified	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1168A>G (p.Ile390Val) results in a conservative amino acid change located in the Heavy metal-associated (HMA) domain (IPR006121) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249556 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1168A>G has been reported in the literature in individuals affected with Wilson Disease (e.g. Dong_2016, Lu_2014). However, several reports also state this variant as a polymorphism (e.g.Tsai_1999, Zhang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001828588	SCV002178539	uncertain significance	Wilson disease	2022-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 390 of the ATP7B protein (p.Ile390Val). This variant is present in population databases (rs770903362, gnomAD 0.02%). This missense change has been observed in individuals with Wilson disease (PMID: 24878384, 27022412). ClinVar contains an entry for this variant (Variation ID: 917697). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002327425	SCV002629992	likely benign	Inborn genetic diseases	2016-10-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV001828588	SCV002782256	uncertain significance	Wilson disease	2022-01-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828588	SCV002087882	uncertain significance	Wilson disease	2020-08-30	no assertion criteria provided	clinical testing