Submissions for variant NM_000053.4(ATP7B):c.2332C>G (p.Arg778Gly)

dbSNP: rs137853284

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000144367	SCV000220896	likely pathogenic	Wilson disease	2014-11-20	criteria provided, single submitter	literature only
Invitae	RCV000144367	SCV000960064	pathogenic	Wilson disease	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 778 of the ATP7B protein (p.Arg778Gly). This variant is present in population databases (rs137853284, gnomAD 0.002%). This missense change has been observed in individual(s) with Wilson disease (PMID: 20517649, 21682854, 23333878). ClinVar contains an entry for this variant (Variation ID: 156283). 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%. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11243728, 11479773, 16998622, 17160357, 23518715). 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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000144367	SCV001149697	pathogenic	Wilson disease	2019-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092072	SCV001248426	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Very Strong, PM1, PM2, PM5, PP3, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000144367	SCV001362720	pathogenic	Wilson disease	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2332C>G (p.Arg778Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246100 control chromosomes (gnomAD). c.2332C>G has been reported in the literature in multiple individuals affected with Wilson Disease (Ferenci_2014). These data indicate that the variant is very likely to be associated with disease. In addition, another variant, c.2332C>T (p.Arg778Trp) affecting the same codon has been classified as pathogenic, therefore, suggesting the importance of this location for ATP7B protein function. 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 pathogenic.
Genome-Nilou Lab	RCV000144367	SCV001977328	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001092072	SCV002032664	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 17272994, 8533760, 24253677, 22692182, 9801873, 11216666, 16207219, 31708252, 32043565, 16283883)
Fulgent Genetics, Fulgent Genetics	RCV000144367	SCV002783869	pathogenic	Wilson disease	2022-02-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000144367	SCV004216397	pathogenic	Wilson disease	2023-06-18	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000144367	SCV000189434	not provided	Wilson disease		no assertion provided	not provided
Natera, Inc.	RCV000144367	SCV001463834	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing