Submissions for variant NM_000053.4(ATP7B):c.1847G>A (p.Arg616Gln)

gnomAD frequency: 0.00001  dbSNP: rs752850609

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667901	SCV000792424	pathogenic	Wilson disease	2017-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667901	SCV000918593	pathogenic	Wilson disease	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246238 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.9e-05 vs 0.0054), allowing no conclusion about variant significance. c.1847G>A has been reported in the literature in multiple individuals affected with Wilson Disease as both a compound heterozygous and homozygous allele (Loudianos_2003, Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. 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.
Invitae	RCV000667901	SCV000933962	pathogenic	Wilson disease	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ATP7B protein (p.Arg616Gln). This variant is present in population databases (rs752850609, gnomAD 0.009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 12885331, 21610751, 22735241, 26799313). ClinVar contains an entry for this variant (Variation ID: 552606). 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%. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000667901	SCV001368970	pathogenic	Wilson disease	2019-04-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3.
CeGaT Center for Human Genetics Tuebingen	RCV001531802	SCV001747089	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000667901	SCV001977361	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000667901	SCV002785645	pathogenic	Wilson disease	2021-08-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000667901	SCV004216308	pathogenic	Wilson disease	2023-10-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001531802	SCV001930734	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001531802	SCV001954808	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000667901	SCV002087861	pathogenic	Wilson disease	2020-07-14	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000667901	SCV004024150	pathogenic	Wilson disease		no assertion criteria provided	research