Submissions for variant NM_000053.4(ATP7B):c.3190G>A (p.Glu1064Lys)

dbSNP: rs376910645

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665883	SCV000790078	likely pathogenic	Wilson disease	2017-03-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508709	SCV001715044	pathogenic	not provided	2019-10-08	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP1, PP3
Genome-Nilou Lab	RCV000665883	SCV001977269	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000665883	SCV002059847	pathogenic	Wilson disease	2019-04-18	criteria provided, single submitter	clinical testing
Invitae	RCV000665883	SCV002233901	pathogenic	Wilson disease	2023-07-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu1064 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15205462, 15723329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ATP7B function (PMID: 18203200, 22240481). 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. ClinVar contains an entry for this variant (Variation ID: 550969). This variant is also known as p.Glu1065Lys. This missense change has been observed in individual(s) with Wilson disease (PMID: 8533760, 15571607, 17272994). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs376910645, gnomAD 0.002%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1064 of the ATP7B protein (p.Glu1064Lys).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000665883	SCV004562683	pathogenic	Wilson disease	2023-10-13	criteria provided, single submitter	clinical testing	The ATP7B c.3190G>A; p.Glu1064Lys variant (rs376910645) is reported in the literature in multiple individuals affected with Wilson disease (Balashova 2020, Figus 1995, Firneisz 2004). This variant is also reported in ClinVar (Variation ID: 550969). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another amino acid substitution at this codon (c.3191A>C; p.Glu1064Ala) has been reported in individuals with Wilson disease and is considered pathogenic (Ala 2005, Morgan 2004, Shah 1997). Functional analyses of the variant protein show that transport activity is ablated (Huster 2012, His 2008). Computational analyses predict that this variant is deleterious (REVEL: 0.958). Based on available information, this variant is considered to be pathogenic. References: Ala A et al. Wilson disease in septuagenarian siblings: Raising the bar for diagnosis. Hepatology. 2005 Mar;41(3):668-70. PMID: 15723329. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Figus A et al. Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet. 1995 Dec;57(6):1318-24. PMID: 8533760. Firneisz G et al. The other mutation is found: follow-up of an exceptional family with Wilson disease. Am J Gastroenterol. 2004 Dec;99(12):2504-5. PMID: 15571607. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Hsi G et al. Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system. Hum Mutat. 2008 Apr;29(4):491-501. PMID: 18203200. Morgan CT et al. The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase: analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem. 2004 Aug 27;279(35):36363-71. PMID: 15205462. Shah et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736.