Submissions for variant NM_000053.4(ATP7B):c.2305A>G (p.Met769Val) (rs193922103)

Total submissions: 10

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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	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	2020-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 769 of the ATP7B protein (p.Met769Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs193922103, ExAC 0.01%). This variant has been reported in the literature in multiple individuals affected with Wilson disease (PMID: 7626145, 20517649, 21610751, 11690702), and has been reported as homozygous in two patients (PMID: 19118915). ClinVar contains an entry for this variant (Variation ID: 35706). This variant has been observed on the opposite chromosome (in trans) from a pathogenic truncating variant in an individual affected with Wilson disease (PMID: 21610751). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies have shown that this missense change has a temperature-dependent activity (PMID: 9837819) and it shows a reduced transport activity (50% relative to normal control ) (PMID: 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.
Baylor Genetics	RCV000029355	SCV001163734	likely pathogenic	Wilson disease		criteria provided, single submitter	clinical testing
Myriad Women's Health, 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	2021-02-17	criteria provided, single submitter	clinical testing	PS4, PS3, PM2, PM5, PP4, PP5
Natera, Inc.	RCV000029355	SCV001463836	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing