Submissions for variant NM_000053.4(ATP7B):c.2827G>A (p.Gly943Ser)

gnomAD frequency: 0.00001  dbSNP: rs28942076

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004060	SCV000694432	pathogenic	Wilson disease	2016-02-16	criteria provided, single submitter	clinical testing	Variant summary: c.2827G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 2/120362 control chromosomes at a frequency of 0.0000166, which does not exceed maximal expected frequency of a pathogenic allele (0.0054006). This variant has been reported in multiple affected individuals and functional studies showed that variant had impaired ability to complement the high-affinity iron-uptake deficiency of the yeast mutant, and despite the normal localization of variant to the Golgi network of CHO cells, variant was non-responsive to copper and exhibited no obvious copper-induced redistribution (Forbes_1998 and 2000). Taken together, this variant was classified as a Pathogenic.
Invitae	RCV000004060	SCV000959367	pathogenic	Wilson disease	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 943 of the ATP7B protein (p.Gly943Ser). This variant is present in population databases (rs28942076, gnomAD 0.007%). This missense change has been observed in individuals with Wilson disease (PMID: 7626145, 11243728, 27022412). ClinVar contains an entry for this variant (Variation ID: 3856). 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: 10942420). This variant disrupts the p.Gly943 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16088907, 16603785, 27930511, 28212618). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001091638	SCV001247797	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	ATP7B: PM2, PM3, PM5, PS4:Moderate, PP4, PS3:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV001091638	SCV001716160	pathogenic	not provided	2020-01-30	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP1, PP4
Genome-Nilou Lab	RCV000004060	SCV001977301	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004060	SCV004216280	pathogenic	Wilson disease	2023-10-21	criteria provided, single submitter	clinical testing
OMIM	RCV000004060	SCV000024226	pathogenic	Wilson disease	1995-02-01	no assertion criteria provided	literature only
Counsyl	RCV000004060	SCV000793725	likely pathogenic	Wilson disease	2019-01-22	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004060	SCV002086842	pathogenic	Wilson disease	2020-10-31	no assertion criteria provided	clinical testing