Submissions for variant NM_000053.4(ATP7B):c.2305A>G (p.Met769Val)

gnomAD frequency: 0.00015  dbSNP: rs193922103

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029355	SCV000052002	pathogenic	Wilson disease	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000029355	SCV000192325	pathogenic	Wilson disease	2017-08-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000078041	SCV000232468	pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000078041	SCV000520885	pathogenic	not provided	2021-07-06	criteria provided, single submitter	clinical testing	Published functional studies found M767V is associated with significantly reduced copper uptake and decreased thermal stability compared to wildtype (Forbes et al., 1998; Huster et al., 2012); 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: 27535533, 31980526, 21610751, 29321352, 10942420, 12557139, 22240481, 11690702, 14986826, 16939419, 17717039, 24253677, 29431110, 19118915, 27022412, 11405812, 10502777, 9311736, 23518715, 22692182, 11093740, 7626145, 20517649, 9837819, 18371106)
Invitae	RCV000029355	SCV000626842	pathogenic	Wilson disease	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 769 of the ATP7B protein (p.Met769Val). This variant is present in population databases (rs193922103, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 7626145, 11690702, 19118915, 20517649, 21610751). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35706). 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: 9837819, 22240481). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029355	SCV001157524	pathogenic	Wilson disease	2019-01-11	criteria provided, single submitter	clinical testing	The ATP7B c.2305A>G; p.Met769Val variant (rs193922103) is reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with Wilson disease (Caca 2001, Curtis 1999, Garcia-Villarreal 2000, Moller 2011, Nicastro 2009, Weiss 2010, Wu 2001). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 35706), and is found in the non-Finnish European population with an allele frequency of 0.016% (20/128,686 alleles) in the Genome Aggregation Database. The methionine at codon 769 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show reduced copper transport activity (Forbes and Cox 1998, Huster 2012). Based on available information, this variant is considered to be pathogenic. References: Caca K et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol. 2001 Nov;35(5):575-81. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. Forbes JR and Cox DW et al. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet. 1998 Dec;63(6):1663-74. Garcia-Villarreal L et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology. 2000 Dec;32(6):1329-36. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. Nicastro E et al. Genotype-phenotype correlation in Italian children with Wilson's disease. J Hepatol. 2009 Mar;50(3):555-61. Weiss KH et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40. Wu ZY et al. Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease. Arch Neurol. 2001 Jun;58(6):971-6.
Myriad Genetics, Inc.	RCV000029355	SCV001193881	pathogenic	Wilson disease	2019-12-24	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.2305A>G(M769V) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 9837819, 19118915, 23518715, 22692182, 24253677, 22240481 and 10942420. Classification of NM_000053.3(ATP7B):c.2305A>G(M769V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078041	SCV001716169	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PM5
Genome-Nilou Lab	RCV000029355	SCV001977330	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000029355	SCV002024419	pathogenic	Wilson disease	2022-12-20	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000078041	SCV002502983	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444440	SCV002734884	pathogenic	Inborn genetic diseases	2017-06-22	criteria provided, single submitter	clinical testing	The p.M769V pathogenic mutation (also known as c.2305A>G), located in coding exon 8 of the ATP7B gene, results from an A to G substitution at nucleotide position 2305. The methionine at codon 769 is replaced by valine, an amino acid with highly similar properties. This mutation was reported in multiple unrelated individuals (Curtis D et al. Hum. Mutat., 1999;14:304-11; García-Villarreal L et al. Hepatology, 2000 Dec;32:1329-36; Caca K et al. J. Hepatol., 2001 Nov;35:575-81; Weiss KH et al. J. Inherit. Metab. Dis., 2010 Dec;33 Suppl 3:S233-40), including two homozygous individuals with hepatic Wilson disease (Nicastro E et al. J. Hepatol., 2009 Mar;50:555-61). Functional studies demonstrated that this mutation impairs the protein function (Forbes JR et al. Am. J. Hum. Genet., 1998 Dec;63:1663-74; Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000029355	SCV002813724	pathogenic	Wilson disease	2022-04-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078041	SCV004010245	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATP7B: PM1, PM2, PM3, PM5, PP3, PS3:Supporting
Baylor Genetics	RCV000029355	SCV001163734	pathogenic	Wilson disease	2022-04-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000029355	SCV001463836	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing