Submissions for variant NM_000053.4(ATP7B):c.2332C>G (p.Arg778Gly) (rs137853284)

Total submissions: 6

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	2018-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glycine at codon 778 of the ATP7B protein (p.Arg778Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 20517649, 21682854, 23333878). ClinVar contains an entry for this variant (Variation ID: 156283). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 11243728, 11479773, 23518715, 17160357, 16998622), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar	RCV000144367	SCV001149697	pathogenic	Wilson disease	2019-01-23	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001092072	SCV001248426	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000144367	SCV000189434	not provided	Wilson disease		no assertion provided	not provided